Submissions for variant NM_174936.4(PCSK9):c.847C>A (p.Leu283Met)

gnomAD frequency: 0.00055  dbSNP: rs72646510

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000382615	SCV000358241	uncertain significance	Hypercholesterolemia, familial, 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000295282	SCV000358242	uncertain significance	Familial hypobetalipoproteinemia	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000775017	SCV000909114	likely benign	Familial hypercholesterolemia	2018-11-14	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the catalytic peptidase domain of the PCSK9 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has the variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant is fairly common in the general African population and has been identified in 36/23294 African chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000861848	SCV001002258	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446543	SCV002677614	likely benign	Cardiovascular phenotype	2023-08-28	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323502	SCV004029946	likely benign	not specified	2023-07-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001699345	SCV004032026	uncertain significance	not provided	2025-01-08	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
CeGaT Center for Human Genetics Tuebingen	RCV001699345	SCV004042433	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	PCSK9: BS1
All of Us Research Program, National Institutes of Health	RCV000861848	SCV004838632	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699345	SCV001918968	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001699345	SCV001963231	uncertain significance	not provided		no assertion criteria provided	clinical testing