Submissions for variant NM_198586.3(NHLRC1):c.478T>C (p.Cys160Arg)

gnomAD frequency: 0.00011  dbSNP: rs200595273

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188213	SCV000241820	uncertain significance	not provided	2017-03-16	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the NHLRC1 gene. The C160R variant has been reported previously in an individual with Lafora disease; however, a second NHLRC1 variant was not detected, and staining failed to detect Lafora inclusion bodies (Singh et al., 2005). The C160R variant is observed in 20/8582 (0.2%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C160R 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. However, this substitution occurs at a position that is not conserved. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001078586	SCV000759833	likely benign	Lafora disease	2023-09-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001078586	SCV001314270	uncertain significance	Lafora disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002517002	SCV003539467	likely benign	Inborn genetic diseases	2021-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001078586	SCV003815905	uncertain significance	Lafora disease	2021-06-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003967481	SCV004785548	likely benign	NHLRC1-related disorder	2020-04-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).