Submissions for variant NM_174936.4(PCSK9):c.525C>T (p.Asp175=)

gnomAD frequency: 0.00117  dbSNP: rs148612296

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587769	SCV000699998	benign	not provided	2017-07-21	criteria provided, single submitter	clinical testing	Variant summary: The PCSK9 c.525C>T (p.Asp175Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may abrogate the binding sites for splicing enhancers. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 44/121334 control chromosomes at a frequency of 0.0003626, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Invitae	RCV001087468	SCV000766244	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776138	SCV000911125	benign	Familial hypercholesterolemia	2018-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000587769	SCV000969265	likely benign	not provided	2020-09-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25904937)
Illumina Laboratory Services, Illumina	RCV001099139	SCV001255562	likely benign	Hypobetalipoproteinemia	2017-10-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001087468	SCV001255563	benign	Hypercholesterolemia, autosomal dominant, 3	2017-10-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587769	SCV002046349	benign	not provided	2020-11-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002341511	SCV002643834	likely benign	Cardiovascular phenotype	2018-02-26	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587769	SCV004564203	benign	not provided	2023-09-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004543307	SCV004771173	likely benign	PCSK9-related disorder	2020-01-13	criteria provided, single submitter	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).
Clinical Genetics, Academic Medical Center	RCV000587769	SCV001917783	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587769	SCV001962839	likely benign	not provided		no assertion criteria provided	clinical testing