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 |
| statementOutcome | @id | 1..1 | The coded pathogenicity of the variant for the condition | SEPIO:0000197 | VariantPathogenicityInterpretation |
| condition | GeneticCondition | 0..* | The condition for which the variant's pathogenicity is described | SEPIO:0000276 | VariantPathogenicityInterpretation |
| assertionMethod | VariantPathogenicityInterpretationGuideline | 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 | statementOutcome | condition | assertionMethod |
|---|---|---|---|---|---|---|---|---|---|
|
NM_002834.3:c.855T>G Pathogenic for Noonan Syndrome |
(Pathogenic) | ||||||||
|
NM_001369.2:c.6249G>A Pathogenic for PCD |
(Pathogenic) | ||||||||
|
NM_004985.4(KRAS):c.173C>T (p.Thr58Ile) Pathogenic for Noonan Syndrome 3 |
(Pathogenic) | ||||||||
|
NM_004985.4(KRAS):c.173C>T (p.Thr58Ile) Pathogenic for Costello syndrome |
(Pathogenic) | ||||||||
|
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. |
(Uncertain Significance) | (ACMG guidelines 2015) | |||||||
|
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. |
(Likely Pathogenic) | ||||||||
|
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. |
(Likely Pathogenic) | (ACMG guidelines 2015) | |||||||
|
Variant has been classified as “Pathogenic” by Sharing Clinical Reports Project (SCV000054057.3) |
(Pathogenic) | ||||||||
|
Variant has been classified as “Pathogenic” by OMIM (SCV000043718.1) |
(Pathogenic) | ||||||||
|
Variant has been classified as “Pathogenic” by Expert panel CFTR (SCV000245981.1) |
(Pathogenic) | ||||||||
|
classified by ENIGMA. |
(Benign) | ||||||||
|
classified by Sharing Clinical Reports Project. |
(Benign) | ||||||||
|
classified by OMIM |
(Benign) | ||||||||
|
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. |
(Uncertain Significance) | ||||||||
|
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. |
(Likely Pathogenic) | (ACMG guidelines 2015) | |||||||
|
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). |
(Benign) | (ACMG guidelines 2015) | |||||||
|
Uncertain Sig(not specified) NM_000363.4(TNNI3):c.484C>T (p.Arg162Trp) |
(Uncertain Significance) | ||||||||
|
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). |
(Likely Benign) | (ACMG guidelines 2015) | |||||||
|
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. |
(Likely Pathogenic) | (ACMG guidelines 2015) | |||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Likely Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Uncertain Significance) | |||||||||
| (Likely Pathogenic) | |||||||||
| (Likely Pathogenic) | |||||||||
| (Likely Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Pathogenic) | |||||||||
| (Likely Pathogenic) | |||||||||
| (Pathogenic) |