ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.1142A>G (p.Asp381Gly) (rs200201752)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188216 SCV000241823 likely pathogenic not provided 2012-12-11 criteria provided, single submitter clinical testing p.Asp381Gly (GAC>GGC): c.1142 A>G in exon 1 of the NHLRC1 gene (NM_198586.2) The Asp381Gly missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This amino acid substitution is non-conservative, as a negatively charged Aspartic acid residue is replaced by an uncharged, non-polar Glycine residue. It alters a highly conserved residue in the sixth NHL domain of the protein, and other missense mutations in this domain have been previously reported in association with Lafora disease. Multiple in silico algorithms predict that Asp381Gly may be damaging to protein structure/function, although one model suggests it may be benign. Therefore, based on the currently available information, Asp381Gly is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be completely excluded. The variant is found in PM-EPI panel(s).
Invitae RCV000707280 SCV000836370 uncertain significance Lafora disease 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 381 of the NHLRC1 protein (p.Asp381Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs200201752, ExAC 0.01%). This variant has not been reported in the literature in individuals with NHLRC1-related disease. ClinVar contains an entry for this variant (Variation ID: 206192). 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. 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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