ClinVar Miner

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

gnomAD frequency: 0.00009  dbSNP: rs141101671
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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.

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