Submissions for variant NM_000527.5(LDLR):c.1124A>G (p.Tyr375Cys)

dbSNP: rs879254800

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237921	SCV000295235	likely 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	RCV000237921	SCV000503302	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 3 , family members = 4 with co-segregation / previously described in association with FH / Software predictions: Damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237921	SCV000583792	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000237921	SCV000607561	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000237921	SCV000894173	pathogenic	Hypercholesterolemia, familial, 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001063149	SCV001227983	pathogenic	Familial hypercholesterolemia	2024-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the LDLR protein (p.Tyr375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9195230, 11668640, 15823288). It has also been observed to segregate with disease in related individuals. This variant is also known as Y354C. ClinVar contains an entry for this variant (Variation ID: 251679). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000237921	SCV001433510	likely pathogenic	Hypercholesterolemia, familial, 1	2019-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436076	SCV002746153	pathogenic	Cardiovascular phenotype	2018-02-23	criteria provided, single submitter	clinical testing	The p.Y375C pathogenic mutation (also known as c.1124A>G), located in coding exon 8 of the LDLR gene, results from an A to G substitution at nucleotide position 1124. The tyrosine at codon 375, in the cbEGF-like #2, is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration, referred to as Y354C, was reported in a pediatric French-Canadian proband with familial hypercholesterolemia (FH), and also segregated with the disease in the family. In addition, reduced LDLR activity was revealed in the proband's fibroblasts (Assouline L et al. Hum. Mutat., 1997;9:555-62). This alteration was also reported in association with FH in other populations (Chaves FJ et al. J. Clin. Endocrinol. Metab., 2001 Oct;86:4926-32; Damgaard D et al. Atherosclerosis, 2005 May;180:155-60). Moreover, an alteration affecting the same amino acid, Y375S, was also described in a child with FH and her affected mother (Mollaki V et al. Ann. Hum. Genet., 2013 Sep;77:426-34). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
PreventionGenetics, part of Exact Sciences	RCV003391007	SCV004119970	pathogenic	LDLR-related disorder	2023-03-31	criteria provided, single submitter	clinical testing	The LDLR c.1124A>G variant is predicted to result in the amino acid substitution p.Tyr375Cys. This variant is also described using legacy nomenclature as p.Tyr354Cys, has been reported to be causative for familial hypercholesterolemia (FH) in multiple individuals (Assouline et al. 1997. PubMed ID: 9195230; García-García et al. 2001. PubMed ID: 11668640; Damgaard et al. 2005. PubMed ID: 15823288). A similar variant, c.1124A>C (p.Tyr375Ser) has also been reported in individuals with FH (Mollaki et al. 2013. PubMed ID: 23815734) suggesting that amino acid residue p.Tyr375 is important for proper LDLR protein function. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.