ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.621C>T (p.Gly207=)

dbSNP: rs121908044
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000003945 SCV000294826 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003945 SCV000503190 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 5, family member = 1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003945 SCV000583711 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003945 SCV000599336 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Iberoamerican FH Network RCV000003945 SCV000748131 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001389663 SCV001591108 pathogenic Familial hypercholesterolemia 2023-10-06 criteria provided, single submitter clinical testing This sequence change affects codon 207 of the LDLR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LDLR protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial hypercholesterolemia (PMID: 18400033, 28104544, 30293936). ClinVar contains an entry for this variant (Variation ID: 3747). Studies have shown that this variant results in the activation of a cryptic splice site in exon 4 (PMID: 18400033). This variant disrupts a region of the LDLR protein in which other variant(s) (p.Glu208Lys) have been determined to be pathogenic (PMID: 1301956, 18677035, 22390909). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV002254902 SCV002526240 pathogenic not provided 2022-06-07 criteria provided, single submitter clinical testing Reported to be one of the most common LDLR variants in FH patients from the Netherlands (Defesche et al., 2008; Kusters et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Published functional studies demonstrate a damaging effect with abnormal gene splicing resulting in the in-frame deletion of 25 amino acids affecting the LDL-receptor class A5 domain (Defesche et al., 2008); Also known as G186=; This variant is associated with the following publications: (PMID: 22390909, 27821657, 18400033, 28104544, 32977124, 30293936, 33740630, 34037665, 21475731)
Ambry Genetics RCV002362561 SCV002659775 pathogenic Cardiovascular phenotype 2021-12-23 criteria provided, single submitter clinical testing The c.621C>T pathogenic mutation (also known as p.G207G), located in coding exon 4, results from a C to T substitution at nucleotide position 621 of the LDLR gene. This nucleotide substitution does not change the amino acid at codon 207. This mutation has been reported in several familial hypercholesterolemia cohorts, and in one of the studies, the average LDL-C level in family members positive for the mutation was elevated compared with relatives who did not carry the alteration (Defesche JC et al. Clin. Genet. 2008;73:573-8; Kusters DM et al. Neth Heart J. 2011;19:175-182; Sánchez-Hernández RM et al. Circ Cardiovasc Genet. 2016;9:504-510; Durst R et al. Atherosclerosis. 2017;257:55-63). In addition, this mutation has been identified in the homozygous state in two unrelated individuals with LDL-C levels indicative of homozygous familial hypercholesterolemia, both of whom suffered myocardial infarction at a young age (Defesche JC et al. Clin. Genet. 2008;73:573-8). RNA studies indicate that the variant creates a cryptic donor splice site in coding exon 4 and results in the in-frame deletion of 25 amino acids in LDL type A repeat 5, which is important for ligand binding (Defesche JC et al. Clin. Genet. 2008;73:573-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology RCV000003945 SCV004175481 pathogenic Hypercholesterolemia, familial, 1 2022-09-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000003945 SCV004848336 pathogenic Hypercholesterolemia, familial, 1 2021-02-22 criteria provided, single submitter clinical testing The p.Gly207Gly variant in LDLR has been reported in >30 individuals with familial hypercholesterolemia (FH) and segregated with disease in numerous affected individuals from several families; of note, at least 2 of these individuals were homozygous and displayed features of autosomal recessive FH (Defesche 2008 PMID: 18400033, Durst 2017 PMID: 28104544, Martín-Campos 2018 PMID: 30293936). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 3747) and was absent from large population studies. Computational tools predict a splicing impact and an in vitro analyses supported an alteration of splicing leading to an in-frame deletion of 75 bp (Defesche 2008 PMID: 18400033, Martin-Campos 2018 PMID: 30293936). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH. ACMG/AMP criteria applied: PS4, PM2_Supporting, PP1_Strong, PS3_Supporting, PM3.
OMIM RCV000003945 SCV000024110 pathogenic Hypercholesterolemia, familial, 1 2008-06-01 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000003945 SCV000606170 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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