ClinVar Miner

Submissions for variant NM_198586.3(NHLRC1):c.103C>G (p.His35Asp) (rs752045674)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188206 SCV000241813 uncertain significance not provided 2013-08-06 criteria provided, single submitter clinical testing p.His35Asp (CAC>GAC): c.103 C>G in exon 1 of the NHLRC1 gene (NM_198586.2) The His35Asp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution of a positively charged Histidine residue with a negatively charged Aspartic acid residue at a position that is not conserved across species. In silico analysis predicts this variant likely has a benign effect on the protein structure/function. Therefore, based on the currently available information, it is unclear whether His35Asp is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI panel(s).
Invitae RCV000638337 SCV000759832 uncertain significance Lafora disease 2017-12-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with aspartic acid at codon 35 of the NHLRC1 protein (p.His35Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. This variant is present in population databases (rs752045674, ExAC 0.03%). This variant has not been reported in the literature in individuals with NHLRC1-related disease. ClinVar contains an entry for this variant (Variation ID: 206184). 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 tolerated, 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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