Submissions for variant NM_002528.7(NTHL1):c.170G>A (p.Arg57His)

gnomAD frequency: 0.00005  dbSNP: rs774831009

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808834	SCV000948957	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 65 of the NTHL1 protein (p.Arg65His). This variant is present in population databases (rs774831009, gnomAD 0.02%). 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: 653125). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001013720	SCV001174343	likely benign	Hereditary cancer-predisposing syndrome	2021-10-14	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	RCV000808834	SCV001781809	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	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
Sema4, Sema4	RCV001013720	SCV002528929	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003411787	SCV004116461	uncertain significance	NTHL1-related disorder	2023-10-11	criteria provided, single submitter	clinical testing	The NTHL1 c.194G>A variant is predicted to result in the amino acid substitution p.Arg65His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2096313-C-T). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/653125/). 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	RCV000808834	SCV005623908	uncertain significance	not provided	2024-07-25	criteria provided, single submitter	clinical testing	The NTHL1 c.194G>A (p.Arg65His) variant has not been reported in the published literature in the germline state in individuals with an NTHL1-related condition. The frequency of this variant in the general population, 0.00016 (3/18386 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.