Submissions for variant NM_002528.7(NTHL1):c.71G>A (p.Cys24Tyr)

gnomAD frequency: 0.00004  dbSNP: rs1034291686

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824649	SCV000965556	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 32 of the NTHL1 protein (p.Cys32Tyr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with NTHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 666205). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV001019545	SCV001180917	likely benign	Hereditary cancer-predisposing syndrome	2024-05-06	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.
GeneDx	RCV000824649	SCV001765419	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003413662	SCV004106455	uncertain significance	NTHL1-related disorder	2023-06-24	criteria provided, single submitter	clinical testing	The NTHL1 c.95G>A variant is predicted to result in the amino acid substitution p.Cys32Tyr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0090% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2097754-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/666205/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000824649	SCV004222236	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The NTHL1 c.95G>A (p.Cys32Tyr) variant has not been reported in individuals with NTHL1-related conditions in the published literature. The frequency of this variant in the general population, 0.0000051 (1/197974 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.