Submissions for variant NM_174936.4(PCSK9):c.1431C>T (p.Cys477=)

gnomAD frequency: 0.00488  dbSNP: rs28362268

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080375	SCV000555880	benign	Hypercholesterolemia, autosomal dominant, 3	2024-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589036	SCV000699987	benign	not provided	2016-08-12	criteria provided, single submitter	clinical testing	Variant summary: The PCSK9 c.1431C>T (p.Cys477Cys) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 192/120408 control chromosomes (3 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.017144 (176/10266). This frequency is about 183 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Taken together, this variant is classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000776072	SCV000910776	benign	Familial hypercholesterolemia	2017-10-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589036	SCV001134564	benign	not provided	2023-04-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001080375	SCV001253984	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	RCV001097683	SCV001253985	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	RCV000589036	SCV001892647	benign	not provided	2019-01-08	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821313	SCV002071581	likely benign	not specified	2018-10-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002393184	SCV002702799	benign	Cardiovascular phenotype	2017-06-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GENinCode PLC	RCV000776072	SCV005077857	benign	Familial hypercholesterolemia	2024-01-12	criteria provided, single submitter	clinical testing