Submissions for variant NM_000527.5(LDLR):c.2292del (p.Ile764fs)

dbSNP: rs875989941

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211606	SCV000295933	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211606	SCV000599407	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811884	SCV000952174	pathogenic	Familial hypercholesterolemia	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile764Metfs*2) 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 heterozygous or homozygous familial hypercholesterolemia (PMID: 1352322, 16159606, 16250003, 16389549, 22883975). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226390). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002444849	SCV002734146	pathogenic	Cardiovascular phenotype	2022-10-18	criteria provided, single submitter	clinical testing	The c.2292delA pathogenic mutation, located in coding exon 15 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 2292, causing a translational frameshift with a predicted alternate stop codon (p.I764Mfs*2). This mutation (also referred to as p.I743Mfs*2, 2292delA or FH-Tyrone) co-occurred in trans with another LDLR mutation in an individual with homozygous familial hypercholesterolemia (HF), and has also been detected in several individuals with heterozygous FH (Webb JC et al. J Lipid Res, 1992 May;33:689-98; Graham CA et al. Atherosclerosis, 1999 Dec;147:309-16; Graham CA et al. Atherosclerosis, 2005 Oct;182:331-40; Fouchier SW et al. Hum Mutat, 2005 Dec;26:550-6; 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). 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.
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211606	SCV000268663	pathogenic	Hypercholesterolemia, familial, 1	2008-06-05	no assertion criteria provided	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000211606	SCV000606627	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research