Submissions for variant NM_002528.7(NTHL1):c.151C>T (p.Arg51Trp)

gnomAD frequency: 0.00004  dbSNP: rs376907606

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813521	SCV000953883	uncertain significance	not provided	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 59 of the NTHL1 protein (p.Arg59Trp). This variant is present in population databases (rs376907606, gnomAD 0.006%). 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: 656985). 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 disruptive. 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	RCV001013001	SCV001173531	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-22	criteria provided, single submitter	clinical testing	The c.175C>T (p.R59W) alteration is located in exon 2 (coding exon 2) of the NTHL1 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000813521	SCV001817285	uncertain significance	not provided	2020-02-07	criteria provided, single submitter	clinical testing	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
Sema4, Sema4	RCV001013001	SCV002528924	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-05	criteria provided, single submitter	curation
Baylor Genetics	RCV003467468	SCV004192125	uncertain significance	Familial adenomatous polyposis 3	2024-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000813521	SCV005623907	uncertain significance	not provided	2024-09-20	criteria provided, single submitter	clinical testing	The NTHL1 c.175C>T (p.Arg59Trp) variant has not been reported in individuals with NTHL1-related conditions in the published literature. The frequency of this variant in the general population, 0.000035 (4/112910 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004751728	SCV005350398	uncertain significance	NTHL1-related disorder	2024-05-31	no assertion criteria provided	clinical testing	The NTHL1 c.175C>T variant is predicted to result in the amino acid substitution p.Arg59Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.