Submissions for variant NM_174936.4(PCSK9):c.1869C>T (p.Thr623=)

gnomAD frequency: 0.00518  dbSNP: rs28362285

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079994	SCV000644866	benign	Hypercholesterolemia, autosomal dominant, 3	2025-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587470	SCV000699989	benign	not provided	2016-07-19	criteria provided, single submitter	clinical testing	Variant summary: The PCSK9 c.1869C>T (p.Thr623Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant along with 4/5 splice tools predicting the variant not to have an impact on splicing. This variant was found in 171/105344 control chromosomes predominantly observed in the African, (1 homozygote) subpopulation at a frequency of 0.0166397 (144/8654). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000188), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. 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. Considering the high prevalence of the variant in the African population, this variant is classified as Benign.
Robarts Research Institute, Western University	RCV000660748	SCV000782983	benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776077	SCV000910812	benign	Familial hypercholesterolemia	2022-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587470	SCV001134567	benign	not provided	2019-06-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079994	SCV001252182	likely benign	Hypercholesterolemia, autosomal dominant, 3	2018-01-13	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	RCV001096000	SCV001252183	likely benign	Hypobetalipoproteinemia	2018-01-13	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.
GeneDx	RCV000587470	SCV001935871	benign	not provided	2019-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413556	SCV002723462	likely benign	Cardiovascular phenotype	2020-03-19	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	RCV000587470	SCV004564013	benign	not provided	2023-11-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001079994	SCV004844499	benign	Hypercholesterolemia, autosomal dominant, 3	2024-02-05	criteria provided, single submitter	clinical testing
GENinCode PLC	RCV000776077	SCV005077861	benign	Familial hypercholesterolemia	2022-08-24	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000587470	SCV005257986	likely benign	not provided		criteria provided, single submitter	not provided