Submissions for variant NM_000527.5(LDLR):c.313_313+1del (rs875989896)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000211607	SCV000294601	pathogenic	Familial hypercholesterolemia 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	Familial hypercholesterolemia 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	Familial hypercholesterolemia 1	2017-03-30	criteria provided, single submitter	clinical testing
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000211607	SCV000599324	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	curation
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000211607	SCV000987703	pathogenic	Familial hypercholesterolemia 1		criteria provided, single submitter	clinical testing
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000211607	SCV000268553	pathogenic	Familial hypercholesterolemia 1	2008-07-09	no assertion criteria provided	clinical testing
Broad Institute Rare Disease Group,Broad Institute	RCV001249011	SCV001422858	likely pathogenic	Familial hypercholesterolemia	2020-01-22	no assertion criteria provided	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).