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

dbSNP: rs112029328

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000213674	SCV000322889	pathogenic	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 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	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249083	SCV001423040	uncertain significance	Familial hypercholesterolemia	2020-01-22	criteria provided, single submitter	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).
Color Diagnostics, LLC DBA Color Health	RCV001249083	SCV001734548	pathogenic	Familial hypercholesterolemia	2020-11-11	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the +1 position of intron 3 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in more than 100 individuals affected with familial hypercholesterolemia (PMID: 10790219, 11668640, 15241806, 16627557, 19318025, 21935675, 22244043, 27784735, 30312929). This variant has been identified in 1/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249083	SCV002511542	pathogenic	Familial hypercholesterolemia	2022-04-05	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.313+1G>C 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. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. c.313+1G>C has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (examples: Mozas_2004, Alonso_2009). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Sevel submitters have classified the variant as likely pathogenic/pathogenic while one has classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001699015	SCV002576992	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22244043, 22390909, 25525159, 19318025, 21935675, 10790219, 11668640, 15241806, 31589614, 32660911, 34037665, 33087929, 7616128)
Ambry Genetics	RCV002321838	SCV002607712	pathogenic	Cardiovascular phenotype	2023-06-30	criteria provided, single submitter	clinical testing	The c.313+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 3 of the LDLR gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration has been reported in multiple familial hypercholesterolemia (FH) patients (Lombardi P et al. J Lipid Res. 1995;36:860-7; Mozas P et al. Hum Mutat. 2000;15:483-4; García-García AB et al. Hum Mutat. 2001;18:458-9). Two other alterations at the same nucleotide position, c.313+1G>A and c.313+1G>T, have also described in individuals with FH, and were shown to cause aberrant splicing as well as attenuated LDLR gene expression (Leren TP et al. Atherosclerosis. 1994;111:175-82; Jensen HK et al. Hum Mutat. 1996;7:269-71; Cameron J et al. Clin Chim Acta. 2009;403:131-5). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001249083	SCV003442662	pathogenic	Familial hypercholesterolemia	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 228358). Disruption of this splice site has been observed in individuals with familial hypercholesterolemia (PMID: 7616128). This variant is present in population databases (rs112029328, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 3 of the LDLR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
PreventionGenetics, part of Exact Sciences	RCV003401129	SCV004105147	pathogenic	LDLR-related condition	2023-07-07	criteria provided, single submitter	clinical testing	The LDLR c.313+1G>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in numerous individuals with familial hypercholesterolemia (Lombardi et al. 1995. PubMed ID: 7616128; Mozas et al. 2000. PubMed ID: 10790219; García-García et al. 2001. PubMed ID: 11668640; Sánchez-Hernández et al. 2016. PubMed ID: 27784735). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11213463-G-C). Variants that disrupt the consensus splice donor site in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000213674	SCV000606075	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Iberoamerican FH Network	RCV000213674	SCV000748173	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV001699015	SCV001921130	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001699015	SCV001963019	pathogenic	not provided		no assertion criteria provided	clinical testing