Submissions for variant NM_000527.5(LDLR):c.1150C>T (p.Gln384Ter)

dbSNP: rs879254805

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237144	SCV000295245	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	RCV000237144	SCV000503304	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237144	SCV000583795	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002519845	SCV003443102	pathogenic	Familial hypercholesterolemia	2022-04-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln384*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 19843101, 33740630). ClinVar contains an entry for this variant (Variation ID: 251688). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000237144	SCV005399091	pathogenic	Hypercholesterolemia, familial, 1	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial hypercholesterolemia 1 (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic individuals have an earlier and more severe onset (Gene Reviews). (I) 0112 - The condition associated with this gene has incomplete penetrance. Recent findings suggest that only 73% of individuals with a heterozygous LDLR pathogenic variant have elevated LDL levels (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Gln363*) in the literature, this is a Cypriot founder mutation and co-segregates with p.(Asp386Glu) in families with familial hypercholesterolemia (PMID: 27578104). It was noted that in two families, this variant was found in isolation, without the missense variant (PMID: 25463123). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV004992121	SCV005612302	pathogenic	Cardiovascular phenotype	2024-08-07	criteria provided, single submitter	clinical testing	The p.Q384* pathogenic mutation (also known as c.1150C>T), located in coding exon 8 of the LDLR gene, results from a C to T substitution at nucleotide position 1150. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This variant (also referred to as p.Q363*) been detected in individuals with features consistent with familial hypercholesterolemia (Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Dedoussis GV et al. Eur J Clin Invest, 2004 Jun;34:402-9; Dedoussis GV et al. Hum Mutat, 2004 Mar;23:285-6; Humphries SE et al. J Mol Med (Berl), 2006 Mar;84:203-14; Taylor A et al. Clin Genet, 2007 Jun;71:561-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.