Submissions for variant NM_002528.7(NTHL1):c.680G>A (p.Gly227Asp)

gnomAD frequency: 0.00001  dbSNP: rs1055874267

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804775	SCV000944700	uncertain significance	not provided	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 235 of the NTHL1 protein (p.Gly235Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). 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: 649768). 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	RCV001025970	SCV001188262	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-07	criteria provided, single submitter	clinical testing	The c.704G>A (p.G235D) alteration is located in exon 4 (coding exon 4) of the NTHL1 gene. This alteration results from a G to A substitution at nucleotide position 704, causing the glycine (G) at amino acid position 235 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000804775	SCV001814475	uncertain significance	not provided	2019-10-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago	RCV001816871	SCV002071881	uncertain significance	not specified	2021-09-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NTHL1 gene demonstrated a sequence change, c.680G>A, in exon 4 that results in an amino acid change, p.Gly227Asp. This sequence change does not appear to have been previously described in individuals with NTHL1-related disorders. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.00041% (dbSNP rs1055874267). The p.Gly227Asp change affects a highly conserved amino acid residue located in a domain of the NTHL1 protein that is known to be functional. The p.Gly227Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Gly227Asp change remains unknown at this time.
Baylor Genetics	RCV001535682	SCV004192087	uncertain significance	Familial adenomatous polyposis 3	2024-03-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001535682	SCV005638580	uncertain significance	Familial adenomatous polyposis 3	2023-12-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001816871	SCV005872919	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535682	SCV001749754	not provided	Familial adenomatous polyposis 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 05-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.