ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1061A>T (p.Asp354Val) (rs755449669)

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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 RCV000237971 SCV000295192 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000771574 SCV000544673 pathogenic Familial hypercholesterolemia 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 354 of the LDLR protein (p.Asp354Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 1301956, 19837725). This variant is also known as Asp333Val in the literature. ClinVar contains an entry for this variant (Variation ID: 251640). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Asp354Ala) has been determined to be pathogenic (PMID: 22698793, 20145306, 20809525). This suggests that the aspartic acid residue is critical for LDLR protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Robarts Research Institute,Western University RCV000237971 SCV000782907 likely pathogenic Familial hypercholesterolemia 1 2018-01-02 criteria provided, single submitter clinical testing
Color RCV000771574 SCV000904158 likely pathogenic Familial hypercholesterolemia 2019-03-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000771574 SCV000917588 likely pathogenic Familial hypercholesterolemia 2018-10-01 criteria provided, single submitter clinical testing Variant summary: LDLR c.1061A>T (p.Asp354Val) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants have been reported as pathogenic or likley pathogenic in the same codon, suggesting a functional role of the codon (c.1061A>G, p.Asp354Gly; c.1061A>C, pAsp354Ala)The variant allele was found at a frequency of 6.5e-05 in 30944 control chromosomes. c.1061A>T has been reported in the literature in an individual affected with Familial Hypercholesterolemia who had reduced LDLR activity (Hobbs_1992). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237971 SCV000606312 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786347 SCV000925129 pathogenic not provided 2017-02-09 no assertion criteria provided provider interpretation Genetic testing: The patient had genetic testing for the familial hypercholesterolemia panel. The test included sequencing of three genes associated with familial hypercholesterolemia: LDLR, APOB, PCSK9 and LDLRAP1. Results showed that the following variant was identified (see report below): p.Asp354Val (c.1061A>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as pathogenic. Given case data, functional studies and other pathogenic variants at this same amino acid (p.Asp354Gly and p.Asp354Ala) we consider this variant likely pathogenic and we feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of FH (not including this patient's family). There is good case data. This variant is historically known as p.Asp333Val. Hobbs, et al., 1992 (PMID: 1301956) reported this variant in a patient of American indian background and had 15-30 % of receptor activity. They classify this variant as a class 5, recycling defect allele. These bind and internalize ligands in coated pits, but fail to release the ligands in the endosome and thus do not recycle to the cell surface. They classify this variant as FH Oklahoma. Wittall, et al., 2010 (PMID: 19837725) reported this in one of their Greek patients with FH. Invitae has also seen this variant in multiple patients with FH. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar: 1.000). The Asp at codon 354 is conserved across species, as are neighboring amino acids. This variant is the first amino acid of the EGF-like 2 calcium binding domain. There is one individual with variation at codon 354 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. This indicates that variants at this position are rare.

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