Submissions for variant NM_000527.5(LDLR):c.519C>A (p.Cys173Ter)

dbSNP: rs769318035

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237782	SCV000294766	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000237782	SCV000484693	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237782	SCV000503174	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family mermbers = 2/previously described in association with FH
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237782	SCV000583690	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237782	SCV000607469	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017544	SCV004847686	pathogenic	Homozygous familial hypercholesterolemia	2019-04-10	criteria provided, single submitter	clinical testing	The p.Cys173X variant (also reported as p.Cys152X in the literature) in LDLR has been reported in the heterozygous state in at least 3 individuals with familial hypercholesterolemia (FH; Vallve 1998, Graham 1999, Wang 2001, ClinVar accession IDs: SCV000484693.1, SCV000503174.1, SCV000583690.1) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 173, which is predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant FH based upon predicted impact to the protein, absence from the general population and case observations. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting.
Ambry Genetics	RCV004020951	SCV005035984	pathogenic	Cardiovascular phenotype	2024-03-14	criteria provided, single submitter	clinical testing	The p.C173* pathogenic mutation (also known as c.519C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 519. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration, also reported as p.C152X, has been reported in familial hypercholesterolemia (FH) cohorts (Graham CA et al. Atherosclerosis, 1999 Dec;147:309-16; Wang J et al. Hum Mutat, 2001 Oct;18:359). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.