ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.694+1G>T

dbSNP: rs879254646
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237951 SCV000294918 likely 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 RCV000237951 SCV000503225 likely pathogenic Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 2 /FH-Corea
Ambry Genetics RCV003165666 SCV003912562 pathogenic Cardiovascular phenotype 2022-12-07 criteria provided, single submitter clinical testing The c.694+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 4 of the LDLR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. 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 variant has been detected in an individual from a familial hypercholesterolemia (FH) cohort (Marduel M et al. Hum Mutat, 2010 Nov;31:E1811-24). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Another variant affecting this splice site (c.694+2T>C) has also been reported in association with FH (Gudnason V et al. Hum. Mutat., 1997;10:36-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp RCV005090218 SCV005837780 pathogenic Familial hypercholesterolemia 2024-05-01 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 4 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with familial hypercholesterolemia (PMID: 9222758, 20809525). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251403). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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