Submissions for variant NM_174936.4(PCSK9):c.1120G>T (p.Asp374Tyr)

dbSNP: rs137852912

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000505195	SCV000599430	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Robarts Research Institute, Western University	RCV000505195	SCV000782972	pathogenic	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000003009	SCV001422592	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2020-01-22	criteria provided, single submitter	curation	The p.Asp374Tyr variant in PCSK9 has been reported in at least 10 families with hypercholesterolemia, segregated with disease in 20 affected relatives from 5 families, and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 2875) as likely pathogenic by the Instituto Nacional de Saude Doutor Ricardo Jorge and as pathogenic by Roberts Research Institute, Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, OMIM, and GeneReviews. In vitro functional studies demonstrating that cells transfected with the variant result in a near complete disappearance of LDLR protein provide some evidence that the p.Asp374Tyr variant may impact protein function (PMID: 19081568, 15772090). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Asp374His, has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 19081568, 26374825/Variation ID: 265939). The p.Asp374Tyr variant is located in a region of PCSK9 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 19081568). In summary, this variant meets criteria to be classified as pathogenic for hypercholesterolemia in an autosomal dominant manner based on the increased prevalence and cosegregation of the variant in affected individuals compared to controls, in vitro functional studies, and computational evidence. ACMG/AMP Criteria applied: PP1_strong, PM2, PS4_moderate, PP3, PM5_supporting, PS3_supporting, PM1_supporting (Richards 2015).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000003009	SCV002768238	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with hypercholesterolemia, familial, 3 (MIM#603776) (PMID: 33173529). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (20 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Peptidase S8 domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been submitted as pathogenic in the ClinVar database, and has been reported in multiple families with familial hypercholesterolaemia (PMID: 14727179, 15099351, 16224054, 28777095). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in multiple families (PMID: 14727179, 15099351, 16224054). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro functional studies show that this variant results in increased binding affinity to LDLR and reduced LDLR protein levels (PMID: 17435765, 19081568). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003009	SCV004292328	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 374 of the PCSK9 protein (p.Asp374Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 14727179, 19797716, 28777095, 33740630). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2875). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCSK9 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 16912035, 18197702, 19081568, 23283366, 27280970). This variant disrupts the p.Asp374 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17765246, 26374825; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017221	SCV004847635	pathogenic	Homozygous familial hypercholesterolemia	2019-04-18	criteria provided, single submitter	clinical testing	The p.Asp374Tyr variant in PCSK9 has been reported in at least 12 individuals with hypercholesterolemia and segregated with disease in at least 9 affected individuals from 1 family (Timms 2004, Humphries 2009, Kaya 2017). It was absent from large population studies, but has been reported in ClinVar (Variation ID: 2875). Computational prediction tools and conservation analysis are consistent with pathogenicity. In vitro functional studies support an impact on protein function (Benjannet 2004, Bottomley 2009, Al-Mashhadi 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS4_Moderate, PP3, PS3_Supporting.
Ambry Genetics	RCV004018541	SCV005001970	pathogenic	Cardiovascular phenotype	2023-10-26	criteria provided, single submitter	clinical testing	The c.1120G>T (p.D374Y) alteration is located in coding exon 7 of the PCSK9 gene. This alteration results from a G to T substitution at nucleotide position 1120, causing the aspartic acid (D) at amino acid position 374 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in numerous individuals with familial hypercholesterolemia (Gill, 2021; Leren, 2021; Kaya, 2017; Humphries, 2009). This variant has also been shown to segregate with disease in multiple affected families (Sun, 2005). This amino acid position is highly conserved in available vertebrate species. Numerous studies have demonstrated that this variant significantly decreases LDL uptake and has significantly increased binding affinity to LDLr compared to wildtype (Larrea-Sebal, 2023; Huijgen, 2021; S&aacute;nchez-Hern&aacute;ndez, 2019; Fasano, 2009). Published structural analyses shows that this variant likely improves the binding affinity of PCSK9 to the LDLr EGF(A) domain (Martin, 2020; Fasano, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000003009	SCV000023167	pathogenic	Hypercholesterolemia, autosomal dominant, 3	2008-02-12	no assertion criteria provided	literature only
GeneReviews	RCV000003009	SCV000490156	not provided	Hypercholesterolemia, autosomal dominant, 3		no assertion provided	literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000505195	SCV000606699	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research