VariantPathogenicityInterpretation

An assertion about the pathogenicity of a genetic sequence variant, based on evaluation of one or more lines of evidence.

SEPIO:0000190
Descended from Statement

Scope and Usage

The generation of variant Interpretations typically follows specific guidelines that include a defined set of 'criteria' specifying how to interpret specific types of information as evidence, and a set of rules ('criterion scoring algorithms') for combining the outcomes of individual criterion assessments to make a final interpretation of a variant's pathogenicity.

Attributes

Name Type Cardinality Description IRI Defined in
variant CanonicalAllele 1..1 The variant whose pathogenicity is being described SEPIO:0000275 VariantPathogenicityInterpretation
condition GeneticCondition 0..* The condition for which the variant's pathogenicity is described SEPIO:0000276 VariantPathogenicityInterpretation
statementOutcome @id 1..1 The coded pathogenicity of the variant for the condition SEPIO:0000197 VariantPathogenicityInterpretation
assertionMethod AssertionMethod 0..1 The framework that formally defines the methodology used in creating this interpretation. SEPIO:0000041 VariantPathogenicityInterpretation
label string 0..1 A name given to the resource. RDFS:label Entity
description string 0..1 Description may include but is not limited to: an abstract, a table of contents, a graphical representation, or a free-text account of the resource. DC:description Entity
userLabelDictionary UserLabel 0..* An optional label defined by the user. Used for custom entities or to clarify the preferred user label on existing entities with non-preferred labels. SEPIO:0000422 Statement
outcomeQualifier string 0..1 Use “NOT” as the value of this property to assert that the statement is negated. SEPIO:0000346 Statement
evidenceLine EvidenceLine 0..* supporting evidence SEPIO:0000006 Statement
contribution Contribution 0..* The contributions (agent, time and role) made to this entity SEPIO:0000159 Statement
source string 0..* A string indicating the source of a Statement DC:source Statement

Instances

ID label description userLabelDictionary outcomeQualifier evidenceLine variant condition statementOutcome assertionMethod

CGEX:VarInterp008

NM_002834.3:c.855T>G Pathogenic for Noonan Syndrome

CAR:CA220155

CGEX:GenCond003

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp009

NM_001369.2:c.6249G>A Pathogenic for PCD

CAR:CA501221

CGEX:GenCond004

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp010

NM_004985.4(KRAS):c.173C>T (p.Thr58Ile) Pathogenic for Noonan Syndrome 3

CAR:CA256480

CGEX:GenCond006

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp011

NM_004985.4(KRAS):c.173C>T (p.Thr58Ile) Pathogenic for Costello syndrome

CAR:CA256480

CGEX:GenCond055

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp055

The Tyr337Cys variant in SOS1 has been reported in 1 individual with clinical features of Noonan syndrome (Roberts 2007), but has also been reported to be present in 2 unaffected individuals from one family (Personal Communication). This variant was absent from large population studies. Studies have shown that the Tyr337Cys variant may impact protein function by increasing its activity though these results are inconclusive and these in vitro assays may not accurately represent biological function (Smith 2013). Due to the conflicting data about this variant, the clinical significance of the Tyr337Cys variant is uncertain.

CGEX:EvLn124

CGEX:EvLn125

CAR:CA090930

CGEX:GenCond075

LOINC:LA26333-7

(Uncertain Significance)

CGEX:AssertMeth331

CGEX:VarInterp060

The Lys483Asn variant in BRAF has not been previously reported in the literature, but has been identified as a de novo variant in one proband in our laboratory. In addition, this residue is highly conserved across evolutionarily distinct species and computational analyses (PolyPhen2, SIFT, AlignGVGD) predict that this variant will impact the normal function of BRAF. It should be noted that the sensitivity and specificity of these computational programs has not been determined by our laboratory. Therefore, this variant is likely to be pathogenic.

CAR:CA273507

CGEX:GenCond049

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp063

The Lys483Gln variant in BRAF has been identified in one proband with clinical features of Cardio-facio-cutaneous syndrome, and was not identified in either of this individual's parents (LMM unpublished data). This variant has not been identified in large population studies. In addition, another variant at the same residue (Lys483Asn) was identified as a de novo variant in an individual with features of a Noonan spectrum disorder (LMM unpublished data). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Lys483Gln variant may impact the normal function of the protein. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.

CGEX:EvLn127

CGEX:EvLn129

CGEX:EvLn131

CAR:CA280055

CGEX:GenCond070

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:AssertMeth331

CGEX:VarInterp150

Variant has been classified as “Pathogenic” by Sharing Clinical Reports Project (SCV000054057.3)

CAR:CA019369

CGEX:GenCond023

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp151

Variant has been classified as “Pathogenic” by OMIM (SCV000043718.1)

CAR:CA128479

CGEX:GenCond024

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp152

Variant has been classified as “Pathogenic” by Expert panel CFTR (SCV000245981.1)

CAR:CA276116

CGEX:GenCond025

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp255

classified by ENIGMA.

CAR:CA276195

CGEX:GenCond073

LOINC:LA6675-8

(Benign)

CGEX:VarInterp256

classified by Sharing Clinical Reports Project.

CAR:CA016113

CGEX:GenCond043

LOINC:LA6675-8

(Benign)

CGEX:VarInterp257

classified by OMIM

CAR:CA113946

CGEX:GenCond044

LOINC:LA6675-8

(Benign)

CGEX:VarInterp270

Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome is caused by a combination of a pathogenic variant in COL2A1 and another in COMP. So CA113 may be involved, but is not the sole cause.

CAR:CA254703

CGEX:GenCond041

LOINC:LA26333-7

(Uncertain Significance)

CGEX:VarInterp274

The Trp2490_Leu2496del variant in DNAH5 leads to an in-frame deletion of 7 amino acids. This variant has been reported together with a second DNAH5 variant (Met2083Ile) in one individual with PCD and situs inversus (Berg 2011). In addition, this variant has been identified in trans configuration with a disease-causing variant in one affected proband (LMM unpublished data). Data from large population studies is insufficient to determine whether this variant is present in the general population. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance.

CGEX:EvLn110

CGEX:EvLn111

CGEX:EvLn112

CAR:CA090919

CGEX:GenCond063

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:AssertMeth331

CGEX:VarInterp041

Arg343His in Exon 08 of LOXHD1: This variant is not expected to have clinical significance because it has been identified in 2.0% (27/1384) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS).

CGEX:EvLn113

CGEX:EvLn114

CGEX:EvLn115

CAR:CA090950

CGEX:GenCond061

LOINC:LA6675-8

(Benign)

CGEX:AssertMeth331

CGEX:VarInterp042

Uncertain Sig(not specified) NM_000363.4(TNNI3):c.484C>T (p.Arg162Trp)

CAR:CA021738

LOINC:LA26333-7

(Uncertain Significance)

CGEX:VarInterp044

p.Tyr109Tyr in exon 4 of MYH7: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has been identified in 0.2% (31/16512) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs36211408).

CGEX:EvLn120

CGEX:EvLn118

CGEX:EvLn119

CAR:CA013536

LOINC:LA26334-5

(Likely Benign)

CGEX:AssertMeth331

CGEX:VarInterp045

The c.631-2A>G variant in DSC2 has been reported in 1 Caucasian individual with ARVC (Heuser 2006). This variant has also been identified by our laboratory in 2 individuals (1 with ARVC and 1 with LVNC). This variant has been reported in 1/66564 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397514042). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and in vitro studies confirmed that it leads to aberrant splicing and reduced DSC2 protein levels (Heuser 2006). Splice and other loss-of-function variants in DSC2 have been reported in individuals with ARVC (http://arvcdatabase.info/). In summary, although additional studies are required to fully establish its clinical significance, the c.631-2A>G variant is likely pathogenic.

CGEX:EvLn121

CGEX:EvLn122

CAR:CA022880

CGEX:GenCond074

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:AssertMeth331

CGEX:VarInterp047

CAR:CA022141

CGEX:GenCond013

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp048

CAR:CA022153

CGEX:GenCond013

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp049

CAR:CA022159

CGEX:GenCond013

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp050

CAR:CA022189

CGEX:GenCond013

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp057

CAR:CA273615

CGEX:GenCond062

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp059

CAR:CA501223

CGEX:GenCond010

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp078

CAR:CA021749

CGEX:GenCond016

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp079

CAR:CA021738

CGEX:GenCond016

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp080

CAR:CA224454

CGEX:GenCond017

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp081

CAR:CA003449

CGEX:GenCond050

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp210

CAR:CA252233

CGEX:GenCond038

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp213

CAR:CA182839

CGEX:GenCond039

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp216

CAR:CA501236

CGEX:GenCond007

LOINC:LA26333-7

(Uncertain Significance)

CGEX:VarInterp243

CAR:CA012381

CGEX:GenCond067

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp247

CAR:CA172240

CGEX:GenCond060

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp248

CAR:CA274460

CGEX:GenCond060

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp251

CAR:CA137502

CGEX:GenCond071

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp254

CAR:CA254703

CGEX:GenCond042

LOINC:LA6668-3

(Pathogenic)

CGEX:VarInterp364

CAR:CA253304

CGEX:GenCond058

LOINC:LA26332-9

(Likely Pathogenic)

CGEX:VarInterp365

CAR:CA273665

CGEX:GenCond058

LOINC:LA6668-3

(Pathogenic)