Submissions for variant NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)

gnomAD frequency: 0.00001  dbSNP: rs875989911

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211642	SCV000295072	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Fundacion Hipercolesterolemia Familiar	RCV000211642	SCV000607528	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV002229197	SCV000752418	pathogenic	Familial hypercholesterolemia	2018-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine with tyrosine at codon 313 of the LDLR protein (p.Cys313Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. For these reasons, this variant has been classified as Pathogenic. This variant affects a cysteine residue located within an LDLRA domain of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). Other missense substitutions at this codon (p.Cys313Arg) have been reported in individuals affected with hypercholesterolemia (PMID: 19318025). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 9259195, 9698020, 11810272, 11857755). This variant is also known as p.Cys292Tyr in the literature. ClinVar contains an entry for this variant (Variation ID: 226339). This variant is not present in population databases (ExAC no frequency).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000211642	SCV000840001	likely pathogenic	Hypercholesterolemia, familial, 1	2018-04-25	criteria provided, single submitter	clinical testing	This c.938G>A (p.Cys313Tyr) variant in the LDLR gene has been reported in multiple familial hypercholesterolemia patients [PMID: 9259195, 11857755, 11810272] but not observed in general population according to gnomad database. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. Multiple in silico predictions suggest this cysteine to tyrosine is deleterious. Multiple variants causing cysteine at amino acid position 313 change to other amino acids have been reported as disease-causing in literature [PMID: 19318025, 15823288, 11257257]. Based upon above evidences, c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826175	SCV000967714	likely pathogenic	Homozygous familial hypercholesterolemia	2019-03-03	criteria provided, single submitter	clinical testing	The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 are in the compound heterozygous state (Day 1997, Thiart 2000, Fouchier 2001, Bunn 2002, Van der Graaf 2011, Martin 2016). It has also been reported in ClinVar (Variation ID: 226339) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys131Tyr variant may impact the protein. This variant is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools do not suggest an impact to splicing. Additionally, other missense variants at this amino acid position (p.Cys313Arg, p.Cys313Gly and p.Cys313Trp) have been reported in individuals with familial hypercholesterolemia (Human Gene Mutation Database: Stenson 2017), suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys313Tyr variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PM2, PP3, PM5_Supporting.
AiLife Diagnostics, AiLife Diagnostics	RCV002223822	SCV002502951	likely pathogenic	not provided	2020-05-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000211642	SCV004822561	likely pathogenic	Hypercholesterolemia, familial, 1	2023-07-11	criteria provided, single submitter	clinical testing	The c.938G>A (p.Cys313Tyr) variant of the LDLR gene has been identified in heterozygous status in multiple (>10) unrelated individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID: 9259195, 9698020, 11040093, 11810272, 11857755, 27680772, 33269076, 23833242, 22883975, 17094996). This variant has also been identified in compound heterozygous status in two individuals with FH (PMID: 21382890). In-silico computational prediction tools suggest that the p.Cys313Tyr variant may have deleterious effect on protein function (REVEL score: 0.979). This variant affects one of the sixty highly conserved cysteine residues located within an LDLR class A or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). This variant is found to be absent in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by several submitters in the ClinVar database (ClinVar ID: 226339). Other amino acid substitutions at the same codon (p.Cys313Gly, p.Cys313Trp) have been classified as likely pathogenic by several ClinVar submitters (ClinVar ID: 251538, 251540). Therefore, the c.938G>A (p.Cys313Tyr) variant in the LDLR gene is classified as likely pathogenic.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211642	SCV000268591	pathogenic	Hypercholesterolemia, familial, 1	2010-03-18	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211642	SCV000606274	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research