Submissions for variant NM_174936.4(PCSK9):c.290G>A (p.Arg97His)

gnomAD frequency: 0.00004  dbSNP: rs376385276

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532903	SCV000644871	likely benign	Hypercholesterolemia, autosomal dominant, 3	2025-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771581	SCV000904165	likely benign	Familial hypercholesterolemia	2022-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194052	SCV001363299	likely benign	not specified	2019-02-04	criteria provided, single submitter	clinical testing	Variant summary: The variant, PCSK9 c.290G>A (p.Arg97His) results in a non-conservative amino acid change located in the propeptide domain (IPR010259) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 277064 control chromosomes, predominantly at a frequency of 0.00078 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.290G>A in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002438425	SCV002746882	likely benign	Cardiovascular phenotype	2022-10-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV000532903	SCV004839827	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-06-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538007	SCV004716709	likely benign	PCSK9-related disorder	2023-09-28	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).