VariantPathogenicityInterpretationCriterion

PS1

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change

SEPIO:0000330

Beware of changes that impact splicing rather than at the amino acid/protein level From CSER paper: One site erroneously used this to apply prior publication of the same exact variant while this rule, as described in more depth on the ACMG/AMP guideline, only applies when the established pathogenic variant has a different nucleotide change than the variant being interpreted.

PS3

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product

SEPIO:0000330

This particular rule will probably be downgraded often, given that there are not many “Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting”

PM1

Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation

SEPIO:0000216

Suggested that this rule is NOT appropriate for LOF variants. Also, note that when the region of interest is a “well-established functional domain” then it’s not necessary to show through evidence that it is intolerant of benign missense variants. However, when a mutational hotspot is being defined, then showing it does not have benign missense variants is important.

PM3

For recessive disorders, detected in trans with a pathogenic variant

SEPIO:0000216

CSER - Laboratories discussed when to modify the strength of PM3, the variant is seen in trans with a pathogenic variant for recessive disorders. Published literature may not always explicitly state the phase of variants found in affected individuals which raises a challenge for invoking PM3. When phase has not been established, some felt that PM3 could be invoked as supporting evidence. Also, if the variant is seen in trans with a pathogenic variant in more than one individual it was felt that PM3 can be upgraded to strong. However, sites did not agree on how many additional observations were necessary to call the evidence strong (2 vs. 3) but concluded that such guidance would be useful. LMM - INCREASES IN STRENGTH IF VARIANT SEEN IN MULTIPLE COMPOUND HETS WITH DIFFERENT LIKELY PATHOGENIC/PATHOGENIC VARIANTS

PM5

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before

SEPIO:0000216

Need to be sure that pathogenic variant exists at the residue in question. Sometimes discrepancy resolution may be required. Some thing like Variantexplorer.org may be useful. Sometimes no assertion is provided in ClinVar ...may require curation by lit. search.