ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)

dbSNP: rs879254746
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238286 SCV002506391 likely pathogenic Hypercholesterolemia, familial, 1 2022-02-09 reviewed by expert panel curation The NM_000527.5 (LDLR): c. 974G>A (p.Cys325Tyr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PM1, PS4_Moderate, PP3, PP4, PS3_Supporting,) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines ( The supporting evidence is as follows: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.977, which is above the threshold of 0.75. PM1 Met: The variant meets PM2, and alters Cys325, which is located in EGF-like 1 domain and is one of 60 highly conserved cysteine residues. PS3_Supporting Met: FACS assay using heterozygous patients’ lymphocytes (level 3 functional assay) showed 50-60% LDLR activity compared to wild type, from one research lab (CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347). PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Moderate Met: Variant meets PM2 and is identified in 8 unrelated index cases. Five of the index cases fulfil DLCN criteria for FH from 5 different laboratories (1 case from Mayo Clinic Atherosclerosis and Lipid genomics Laboratory, LabID500068; 1 case from University of Genova-University of Modena and Reggio Emilia, Italy, PMID32977124; 1 case from Lipid Clinic, Fundación Jiménez Díaz, Spain, PMID19318025; 1 case from Centre for Heart Lung Innovation, University of British Columbia, Canada, PMID31345425; and 1case from Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, China, PMID30526649). One index case fulfil FH diagnosis criteria established by the Societa Italiana per lo Studio della Arteriosclerosi, CEINGE-Biotecnologie Avanzate, Napoli, Italy, PMID21865347. Two index cases fulfil Japanese FH guidelines, from Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan, PMID31491741. There are three other variants in the same codon: LDLR: NM_000527: c.973T>C (p.Cys325Arg), LDLR: NM_000527: c.974G>C (p.Cys325Ser), LDLR: NM_000527: c.974G>T (p.Cys325Phe), which are classified as Uncertain significance by these guidelines. Therefore PM5 is not met.
LDLR-LOVD, British Heart Foundation RCV000238286 SCV000295121 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000238286 SCV000607539 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588581 SCV000697256 likely pathogenic Familial hypercholesterolemia 2022-05-02 criteria provided, single submitter clinical testing Variant summary: LDLR c.974G>A (p.Cys325Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Cys325 is a highly conserved residue located in the EGF-like calcium-binding domain of the LDL receptor. HGMD lists >50 Cys missense mutations reported in the literature as associated with hypercholesterolaemia, and five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251090 control chromosomes (gnomAD). c.974G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and coronary artery disease (Romano_2011, Alonso_2009, Rubba_2017, Cao_2018, Trinder_2019, Hori_2019, Di Taranto_2020, Wang_2020, Bertolini_2020, Doi_2021), including at least two homozygotes. One of homozygous patients had this variant in cis with c.[974G>A];[(940+1_941-1)_(2311+1_2312-1)dup (Gly314_Gln770dup, described as pathogenic) (Di Taranto_2020). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact on protein function and shown to have significantly decreased LDLR residual activity in EBV-transformed B-lymphocytes and stimulated T-lymphocytes (Romano_LDLR_JLR_2011, Bertolini_2020). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1), likely pathogenic (n=3) and uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238286 SCV001432620 pathogenic Hypercholesterolemia, familial, 1 2019-06-05 criteria provided, single submitter research
Invitae RCV000588581 SCV001544522 uncertain significance Familial hypercholesterolemia 2021-09-01 criteria provided, single submitter clinical testing
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000238286 SCV001653614 likely pathogenic Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing Reduced activity, in stimulated T-lymphocytes and EBV-transformed B-lymphocytes.
GeneDx RCV002256181 SCV002526591 likely pathogenic not provided 2022-06-16 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect with reduced LDLR activity compared to wild type (Romano et al., 2011); This variant is associated with the following publications: (PMID: 30526649, 19318025, 21865347, 31491741, 32977124)

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