ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1307T>C (p.Val436Ala) (rs779732323)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237902 SCV000295357 uncertain significance Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000489496 SCV000576707 likely pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing The V436A likely pathogenic variant in the LDLR gene has been previously reported in association with FH (Lombardi et al., 1997; Vaca et al., 2011). Lombardi et al. (1997) originally published a case report in which V436A (alternate nomenclature of V415A) was identified in a Dutch proband with FH; the variant was also present in 10 relatives clinically diagnosed with FH, and absent in 11 other relatives without evidence of hypercholesterolemia. However, because a pedigree was not provided in this report, the exact relationship of tested relatives to the proband could not be determined (Lombardi et al., 1997). Subsequently, Vaca et al. (2011) identified V436A in a Mexican proband with FH. The V436A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). V436A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position where only amino acids with similar properties to valine are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, V436A is located in the LDL-receptor class B repeat functional domain, which is critical for ligand release and recycling of the receptor (Davis et al., 1987).
Iberoamerican FH Network RCV000237902 SCV000748053 uncertain significance Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV001063423 SCV001228267 uncertain significance Familial hypercholesterolemia 2019-11-05 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 436 of the LDLR protein (p.Val436Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs779732323, ExAC 0.002%). This variant has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 9184256, 21722902, 21382890, Invitae). This variant is also known as V415A in the literature. ClinVar contains an entry for this variant (Variation ID: 251778). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Color Health, Inc RCV001063423 SCV001733658 likely pathogenic Familial hypercholesterolemia 2020-12-13 criteria provided, single submitter clinical testing This missense variant (also known as p.Val415Ala in the mature protein) replaces valine with alanine at codon 436 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in over 45 individuals affected with hypercholesterolemia, including 42 Dutch carriers with LDL-C levels in the 75-88th percentile (PMID: 9184256, 21382890, 21722902; Hartgers 2020, dissertation, University of Amsterdam). This variant has been reported to segregate with hypercholesterolemia in ten individuals from a Dutch family (PMID: 9184256). This variant has been identified in 4/282608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237902 SCV000606390 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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