Submissions for variant NM_000527.5(LDLR):c.313+1G>C (rs112029328)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000844754	SCV000271389	pathogenic	Homozygous familial hypercholesterolemia	2019-06-07	criteria provided, single submitter	clinical testing	The c.313+1G>C variant in LDLR has been identified in >80 Spanish individuals with familial hypercholesterolemia (FH; Tejedor 2011). It has also been identified in 1/113710 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for FH in an autosomal dominant manner. PVS1_Strong, PS4, PM2.
LDLR-LOVD, British Heart Foundation	RCV000213674	SCV000294605	likely pathogenic	Familial hypercholesterolemia 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000213674	SCV000322889	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles; 0/32 normolipidemic individuals; 0/60 healthy control individuals
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000213674	SCV000503134	pathogenic	Familial hypercholesterolemia 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1
Fundacion Hipercolesterolemia Familiar	RCV000213674	SCV000607444	pathogenic	Familial hypercholesterolemia 1	2016-03-01	criteria provided, single submitter	research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum	RCV000213674	SCV000606075	pathogenic	Familial hypercholesterolemia 1		no assertion criteria provided	research
Iberoamerican FH Network	RCV000213674	SCV000748173	pathogenic	Familial hypercholesterolemia 1	2016-03-01	no assertion criteria provided	research
Broad Institute Rare Disease Group,Broad Institute	RCV001249083	SCV001423040	uncertain significance	Familial hypercholesterolemia	2020-01-22	no assertion criteria provided	curation	The c.313+1G>C variant in LDLR has been reported in at least 5 Spanish and/or Dutch individuals with familial hypercholesterolemia (PMID: 21935675, 7616128, 10790219), and has been identified in 0.0009% (1/113710) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112029328). This variant has also been reported in ClinVar as both pathogenic and likely pathogenic (Variation ID: 228358). This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. 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. Heterozygous loss of function of the LDLR gene is an established disease mechanism in familial hypercholesterolemia. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PS4_supporting (Richards 2015).