ClinVar Miner

Submissions for variant NM_002528.7(NTHL1):c.145C>T (p.Arg49Cys)

gnomAD frequency: 0.00001  dbSNP: rs371105614
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000809525 SCV000949678 uncertain significance not provided 2025-01-12 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 57 of the NTHL1 protein (p.Arg57Cys). This variant is present in population databases (rs371105614, gnomAD 0.004%). 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: 653714). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine 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.
GeneDx RCV000809525 SCV001818138 uncertain significance not provided 2024-03-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 8990169, 9045706, 9705289)
Ambry Genetics RCV002397662 SCV002714070 likely benign Hereditary cancer-predisposing syndrome 2023-12-27 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.
Baylor Genetics RCV003467434 SCV004192118 uncertain significance Familial adenomatous polyposis 3 2024-03-09 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004751723 SCV005347083 uncertain significance NTHL1-related disorder 2024-09-11 no assertion criteria provided clinical testing The NTHL1 c.169C>T variant is predicted to result in the amino acid substitution p.Arg57Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/653714/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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