ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr) (rs879255066)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237476 SCV000295736 likely 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 RCV000237476 SCV000503429 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH (linked to ethnicity ?)/software prediction damaging
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237476 SCV000583903 likely pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Iberoamerican FH Network RCV000237476 SCV000748101 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001048311 SCV001212307 pathogenic Familial hypercholesterolemia 2019-01-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 627 of the LDLR protein (p.Ala627Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia (PMID: 7903864, 27830735, 9763532, 25807990, 23375686, 23158915, 27206935, 30108616, 28235710, 21376320, 28502510). This variant is also described as p.Ala606Thr in the literature. ClinVar contains an entry for this variant (Variation ID: 252101). This variant has been reported to affect LDLR protein function (PMID: 7903864). This variant disrupts the p.Ala627 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Color RCV001048311 SCV001355020 likely pathogenic Familial hypercholesterolemia 2019-06-06 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000237476 SCV001422631 uncertain significance Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Ala627Thr variant in LDLR has been reported in 6 individuals with Familial Hypercholesterolemia (PMID: 7903864, 20538126, 27830735, 19020990, 28502510; Variation ID: 252101), segregated with disease in 2 affected relatives from 1 family and has been identified in 0.005437% (1/18394) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs879255066). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 252101). In vitro functional studies provide some evidence that the p.Ala627Thr variant may slightly impact protein processing and binding affinity (PMID: 7903864). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_supporting, PP3, PS4_Supporting (Richards 2015).

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