Submissions for variant NM_005236.3(ERCC4):c.703G>A (p.Ala235Thr)

gnomAD frequency: 0.00009  dbSNP: rs141101671

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800805	SCV000940541	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2023-09-19	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC4 protein function. ClinVar contains an entry for this variant (Variation ID: 646508). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (rs141101671, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 235 of the ERCC4 protein (p.Ala235Thr).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003238225	SCV002009691	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816859	SCV002070303	uncertain significance	not specified	2021-12-23	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in individuals with ERCC4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.011% (dbSNP rs141101671). The p.Ala235Thr change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Ala235Thr substitution appears to be benign 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.Ala235Thr change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV002495066	SCV002799754	uncertain significance	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2022-04-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002534657	SCV003548928	uncertain significance	Inborn genetic diseases	2022-04-12	criteria provided, single submitter	clinical testing	The c.703G>A (p.A235T) alteration is located in exon 4 (coding exon 4) of the ERCC4 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the alanine (A) at amino acid position 235 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV003238225	SCV005327649	uncertain significance	not provided	2023-10-04	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