Submissions for variant NM_174936.4(PCSK9):c.1504-5_1504-4del

dbSNP: rs755817854

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000542573	SCV000644863	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776502	SCV000912084	likely benign	Familial hypercholesterolemia	2017-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293574	SCV001482180	benign	not specified	2021-02-15	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1504-5_1504-4delCT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00031 in 167486 control chromosomes. The observed variant frequency is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1504-5_1504-4delCT in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001293574	SCV002046238	benign	not specified	2020-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002395410	SCV002700586	likely benign	Cardiovascular phenotype	2018-02-08	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.
CeGaT Center for Human Genetics Tuebingen	RCV003456412	SCV004185021	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	PCSK9: BP4, BS1, BS2
All of Us Research Program, National Institutes of Health	RCV000542573	SCV004823282	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-05	criteria provided, single submitter	clinical testing
GeneDx	RCV003456412	SCV005377730	uncertain significance	not provided	2024-04-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.