ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.805G>A (p.Val269Met) (rs140164729)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188220 SCV000241827 uncertain significance not provided 2014-09-18 criteria provided, single submitter clinical testing p.Val269Met (GTG>ATG): c.805 G>A in exon 1 of the NHLRC1 gene (NM_198586.2). A variant of unknown significance has been identified in the NHLRC1 gene. The V269M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is conserved through mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (L261P abd L279P) have been reported in association with Lafora disease, supporting the functional importance of this region of the protein. However, the V269M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Invitae RCV001050548 SCV001214663 uncertain significance Lafora disease 2019-03-15 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 269 of the NHLRC1 protein (p.Val269Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs140164729, ExAC 0.02%). This variant has not been reported in the literature in individuals with NHLRC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 206196). 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 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.

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