ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.299A>T (p.Asp100Val) (rs879254460)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Robarts Research Institute,Western University RCV000408769 SCV000484769 uncertain significance Familial hypercholesterolemia 1 2019-08-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000776496 SCV000912078 uncertain significance Familial hypercholesterolemia 2019-04-02 criteria provided, single submitter clinical testing
Invitae RCV000776496 SCV001214896 uncertain significance Familial hypercholesterolemia 2020-03-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 100 of the LDLR protein (p.Asp100Val). 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 observed in individual(s) with clinical features of familial hypercholesterolemia or early-onset myocardial infarction (PMID: 27765764, 30586733, Invitae). ClinVar contains an entry for this variant (Variation ID: 369854). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). This variant disrupts the p.Asp100 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 25936346), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000408769 SCV001440063 likely pathogenic Familial hypercholesterolemia 1 2019-01-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786356 SCV000925142 uncertain significance not provided 2016-08-11 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 and PCSK9 and deletion/duplication analysis for the LDLR gene. p.Asp200Val (c.299A>T) in the LDLR gene (NM_000527.4) The lab classifies this variant as a variant, likely pathogenic. Given a lack of case data for this specific variant, in combination with in-silico tools and the knowledge that there are two other pathogenic variants that have been identified at this amino acid (D100N and D100E) we consider this variant of unknown significance, but likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing") in combination with a full lipid panel. The specific variant has not been reported before in individuals with familial hypercholesterolemia (not including this patient's family). However, two other variants have been seen at the same amino acid (D100N and D100E). Both of these changes are listed as pathogenic. This change falls within a turn motif of the protein that includes amino acids 99-103. The native, acidic aspartic acid at the 100th aa position is substituted by a valine which is hydrophobic and small in size. The other two variants that have been found at this position include substitutions with a an amide of similar structure (D100N) and a glutamic acid which has a larger structure and an acidic nature (D100E). In silico analysis with PolyPhen-2 predicts the variant to be pathogenic (HumVar: 1.00) as does mutation taster (0.999). The aspartic acid at codon 100 is conserved across species. There is no variation at codon 100 listed in the Exome Aggregation Consortium dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 11, 2016). The average coverage at that site in ExAC is 30x.

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