ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000003883 SCV000264001 likely pathogenic Familial hypercholesterolemia 1 2015-09-17 criteria provided, single submitter clinical testing
LDLR-LOVD, British Heart Foundation RCV000003883 SCV000295346 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000003883 SCV000322941 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles; 0/100 Chinese normolipidemic individuals; 0/100 healthy control individuals
Robarts Research Institute,Western University RCV000003883 SCV000484702 likely pathogenic Familial hypercholesterolemia 1 criteria provided, single submitter clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies,APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000003883 SCV000503329 likely pathogenic Familial hypercholesterolemia 1 2016-12-16 criteria provided, single submitter clinical testing subjects mutated among 2600 FH index cases screened = 4 , family members = 11 with co-segregation / FH-Algeria-2, 5 to 15% LDLR activity / Software predictions: Damaging
Molecular Genetics Laboratory,Centre for Cardiovascular Surgery and Transplantation RCV000003883 SCV000540810 likely pathogenic Familial hypercholesterolemia 1 2016-11-05 criteria provided, single submitter clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000003883 SCV000583817 pathogenic Familial hypercholesterolemia 1 2017-03-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000003883 SCV000588572 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Fundacion Hipercolesterolemia Familiar RCV000003883 SCV000607581 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Iberoamerican FH Network RCV000003883 SCV000748145 pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000806811 SCV000946830 pathogenic Familial hypercholesterolemia 2019-03-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 431 of the LDLR protein (p.Ala431Thr). 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 affected with familial hypercholesterolemia (FH), including individuals with homozygous FH (HoFH) (PMID: 12837857, 21382890, 25461735, 17765246, 10447263, 27824480, 17347910, 23815734, 15200491, 28104544). This variant is also described as Ala410Thr (A410T) in the literature. ClinVar contains an entry for this variant (Variation ID: 3695). Experimental studies have shown that this missense change leads to a reduction in LDL receptor amount and activity (PMID: 12837857). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985760 SCV001134248 likely pathogenic not provided 2019-05-28 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Integrated Genetics/Laboratory Corporation of America RCV000806811 SCV001338225 pathogenic Familial hypercholesterolemia 2020-02-28 criteria provided, single submitter clinical testing Variant summary: LDLR c.1291G>A (p.Ala431Thr) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251286 control chromosomes (gnomAD). c.1291G>A has been reported in the literature in multiple individuals, (in heterozygous, compound heterozygous and homozygous states), of different origins (e.g. Algerian, Chinese, Dutch, Greek, Japanese, Portuguese), affected with Familial Hypercholesterolemia (e.g. Bourbon_2008, Chang_2003, Dedoussis_2004, Hattori_1999, Hobbs_1992, Kusters_2013) and has been shown to co-segregate with disease in multiple families (e.g. Medeiros_2014, Mollaki_2014). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was reported to have considerably reduced LDLR activity compared to wild-type and was found to be retained in the endosomal/lysosomal region in contrast to the wild-type protein which localizes to the cell surface (Chang_ 2003, Hobbs_1992). Twelve ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000003883 SCV001432625 pathogenic Familial hypercholesterolemia 1 2019-05-23 criteria provided, single submitter research
OMIM RCV000003883 SCV000024048 pathogenic Familial hypercholesterolemia 1 2014-08-27 no assertion criteria provided literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000003883 SCV000606382 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000003883 SCV000733819 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000003883 SCV001422931 pathogenic Familial hypercholesterolemia 1 2020-01-22 no assertion criteria provided curation The p.Ala431Thr (sometimes called p.Ala410Thr) variant in LDLR has been reported in at least 224 individuals (including 190 Dutch, 25 Portuguese, 2 Polish, 1 Greek, 1 Taiwanese, 1 Chinese, 1 Czech, and 1 Japanese individuals) with Familial Hypercholesterolemia (PMID: 20506408, 21382890, 17347910, 12837857, 22698793, 20538126, 20145306, 2088165, 10447263, 17765246, 15200491, 11810272), and has been identified in 0.005439% (1/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs28942079). 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 and pathogenic in ClinVar (Variation ID: 3695). Trio exome analysis showed this variant to be de novo in at least one individual reported in the literature (PMID: 17765246). In vitro functional studies provide some evidence that the p.Ala431Thr variant may impact protein function (PMID: 12837857, 2088165). 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, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on a report of a de novo occurrence and multiple reports of this variant in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PS2, PS4, PS3_Moderate, PP3 (Richards 2015).

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