Submissions for variant NM_174936.4(PCSK9):c.1395G>A (p.Ser465=)

gnomAD frequency: 0.00289  dbSNP: rs146960060

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587347	SCV000699986	benign	not provided	2016-05-05	criteria provided, single submitter	clinical testing	Variant summary: The PCSK9 variant, c.1395G>A (p.Ser465Ser) causes a synonymous change involving a non-conserved nucleotide with 5/5 in silico programs via Alamut predicting no significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 118/121334 (1/1028), predominantly in the African cohort, 112/10394 (1/92), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic PCSK9 variant of 1/53191. Therefore, suggesting that the variant is a common polymorphism found in population(s) of African origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications and/or reputable clinical laboratories/databases. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Invitae	RCV001083746	SCV000766254	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776125	SCV000911055	benign	Familial hypercholesterolemia	2017-11-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000587347	SCV001784902	likely benign	not provided	2021-11-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821715	SCV002067194	likely benign	not specified	2018-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395512	SCV002697124	benign	Cardiovascular phenotype	2018-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587347	SCV004222365	benign	not provided	2023-04-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001083746	SCV004842459	benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-05	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000776125	SCV005062052	benign	Familial hypercholesterolemia	2022-07-07	criteria provided, single submitter	clinical testing