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

dbSNP: rs112029328

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238235	SCV000294606	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000238235	SCV000322890	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/208 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000238235	SCV000503131	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family member=1/FH-Europe
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017540	SCV004847682	likely pathogenic	Homozygous familial hypercholesterolemia	2019-04-16	criteria provided, single submitter	clinical testing	The c.313+1G>T variant in LDLR has been reported in 3 individuals with familial hypercholesterolemia (FH; Jensen 1996, Graham 2005). It has also been identified in 0.003% (1/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 251134). This variant occurs within the canonical splice site (+/- 1,2) and is predicted by in vitro studies to cause altered splicing that would preserve the protein reading frame, leading to an abnormal protein (Jensen 1996). Two additional variants involving the +1 canonical splice site (c.313+1G>C, c.313+1G>A) have been identified in individuals with FH and have been classified as pathogenic by other clinical laboratories (including this laboratory). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1_Moderate, PM2, PS1, PS4_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800359	SCV005423499	pathogenic	Familial hypercholesterolemia	2024-10-02	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.313+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of LDLR function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. c.313+1G>T has been reported in the literature in multiple hererozygous individuals affected with Familial Hypercholesterolemia (Jensen_1996). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8829662, 34011801, 36648309). ClinVar contains an entry for this variant (Variation ID: 251134). Based on the evidence outlined above, the variant was classified as pathogenic.