Submissions for variant NM_000527.5(LDLR):c.313_313+1del

dbSNP: rs875989896

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211607	SCV000294601	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	RCV000211607	SCV000503130	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 , family members = 2
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000211607	SCV000583653	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	Updated according to ClinGen VCEP Guidelines (2022) for LDLR variant classification in FH (PMID: 34906454). This frameshift mutation is estimated to generate truncated protein products deprived of most of their functional domains (PVS1). In addition, this deletion abolishes the canonical donor splice site of intron 3, without potentially creating any alternate donor splice site in close vicinity (PP3). It was shown by in-vitro studies (PS3 moderate) to abolish protein expression in homozygous carriers (FH Lille Allele). Mutation recurrently causing FH diagnosed by validated clinical criteria reported in multiple Disease Specific Databases for several decades (PS4) . Absent from Large General Population Databases (PM2 Strong). More than 10 index cases from the Lille registry had a clinical scoring of Definite FH (DLCN Score >8). This clinical scoring level is highly specific (90%) for a carrier status of a pathogenic LDLR mutation causative of FH (PP4 Strong).
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211607	SCV000599324	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	curation
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000211607	SCV000987703	pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249011	SCV001422858	likely pathogenic	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	curation	The c.313_313+1delCG variant in LDLR has been reported in 1 Australian and 1 French individual with familial hypercholesterolemia (PMID: 22883975, 1301956), and was absent from large population studies. This variant has also been reported in ClinVar as pathogenic (Variation ID: 226316). In vitro functional studies provide some evidence that the c.313_313+1delCG variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence, deletes the last base of the exon inducing a frameshift, and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. There is an in-frame cryptic splice site within 6 basepairs of the intron-exon boundary that could result in a rescued transcript and may maintain function of LDLR. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_supporting, PS4_supporting, PVS1_moderate, PM2 (Richards 2015).
MGZ Medical Genetics Center	RCV000211607	SCV002580841	likely pathogenic	Hypercholesterolemia, familial, 1	2022-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV002469073	SCV002765862	pathogenic	not provided	2022-06-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect as cell cultures from a homozygous patient show 2-5% residual LDL receptor activity (Hobbs et al., 1992); Canonical splice site variant expected to result in aberrant splicing; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Also known as FH Lille; This variant is associated with the following publications: (PMID: 1301956, 33087929, 22883975)
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211607	SCV000268553	pathogenic	Hypercholesterolemia, familial, 1	2008-07-09	no assertion criteria provided	clinical testing