Submissions for variant NM_000122.2(ERCC3):c.385G>A (p.Val129Ile)

gnomAD frequency: 0.00005  dbSNP: rs145762413

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000290626	SCV000416348	uncertain significance	Xeroderma pigmentosum group B	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Baylor Genetics	RCV001828326	SCV002096966	uncertain significance	Trichothiodystrophy 2, photosensitive	2022-01-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV001859962	SCV002224551	uncertain significance	not provided	2022-08-20	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 331091). This variant has not been reported in the literature in individuals affected with ERCC3-related conditions. This variant is present in population databases (rs145762413, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the ERCC3 protein (p.Val129Ile).
Sema4, Sema4	RCV002256209	SCV002532631	uncertain significance	Xeroderma pigmentosum	2022-03-04	criteria provided, single submitter	curation
GeneDx	RCV001859962	SCV002584283	uncertain significance	not provided	2022-04-13	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
Ambry Genetics	RCV002521284	SCV003705702	uncertain significance	Inborn genetic diseases	2022-09-06	criteria provided, single submitter	clinical testing	The c.385G>A (p.V129I) alteration is located in exon 3 (coding exon 3) of the ERCC3 gene. This alteration results from a G to A substitution at nucleotide position 385, causing the valine (V) at amino acid position 129 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.