Submissions for variant NM_174936.4(PCSK9):c.1099G>C (p.Asp367His)

dbSNP: rs141867978

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000952223	SCV001098707	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-10-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000952223	SCV001253877	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001097586	SCV001253878	likely benign	Hypobetalipoproteinemia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001181285	SCV001346396	likely benign	Familial hypercholesterolemia	2019-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001560434	SCV001782847	uncertain significance	not provided	2021-01-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar (ClinVar Variant ID# 772622; Landrum et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Phosphorus, Inc.	RCV001823750	SCV002073427	uncertain significance	not specified	2022-01-14	criteria provided, single submitter	clinical testing	This missense variant results in an amino acid substitution of Aspartic acid with Histidine at codon 367 of the PCSK9 gene (transcript: NM_174936.3). This variant has an entry in ClinVar (772622) NM_174936.4(PCSK9):c.1099G>C (p.Asp367His). This variant occurred in gnomAD with a total MAF of 0 0.0232% and with the highest MAF of 0.1819% in the South Asian population. This position is not conserved. In silico functional algorithms disagree and predict this variant to be probably damaging (PolyPhen) and tolerated (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has not occurred in the literature in association with the disease. Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance.
Ambry Genetics	RCV002445104	SCV002732252	likely benign	Cardiovascular phenotype	2022-05-31	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	RCV001823750	SCV004029942	likely benign	not specified	2023-07-18	criteria provided, single submitter	clinical testing