Submissions for variant NM_174936.4(PCSK9):c.1354+9G>T

gnomAD frequency: 0.00337  dbSNP: rs72646516

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001101341	SCV000555873	benign	Hypercholesterolemia, autosomal dominant, 3	2025-01-26	criteria provided, single submitter	clinical testing
Robarts Research Institute, Western University	RCV000660743	SCV000782976	uncertain significance	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101340	SCV001257941	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.
Illumina Laboratory Services, Illumina	RCV001101341	SCV001257942	likely benign	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 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174797	SCV001338142	benign	not specified	2020-02-03	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1354+9G>T alters a conserved 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 0.001 in 246862 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 128-fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (9.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. A co-occurrence with a pathogenic variant has been reported (LDLR c.1898G>T, p.Arg633Leu; internal testing), providing supporting evidence for a benign role. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and as benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001174797	SCV002773915	benign	not specified	2021-07-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114596	SCV003799397	benign	not provided	2023-09-22	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV004577948	SCV005062050	benign	Familial hypercholesterolemia	2023-08-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004539969	SCV004779567	likely benign	PCSK9-related disorder	2021-05-17	no assertion criteria provided	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).