ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.178C>T (p.His60Tyr) (rs539307365)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000520672 SCV000617111 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NHLRC1 gene. The H60Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H60Y variant is observed in 4/4656 (0.1%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H60Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. Multiple missense variants in nearby residues have been reported in Human Gene Mutation Database in association with autosomal recessive Lafora disease (LD) (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001055166 SCV001219540 uncertain significance Lafora disease 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 60 of the NHLRC1 protein (p.His60Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs539307365, ExAC 0.09%). This variant has not been reported in the literature in individuals with NHLRC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 449234). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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