Submissions for variant NM_000123.4(ERCC5):c.542A>G (p.His181Arg)

gnomAD frequency: 0.00024  dbSNP: rs4150295

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000323906	SCV000382087	uncertain significance	Xeroderma pigmentosum, group G	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.
GeneDx	RCV001764279	SCV002000852	uncertain significance	not provided	2022-01-19	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
Invitae	RCV001764279	SCV002147808	uncertain significance	not provided	2022-05-21	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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 310914). This variant has not been reported in the literature in individuals affected with ERCC5-related conditions. This variant is present in population databases (rs4150295, gnomAD 0.05%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 181 of the ERCC5 protein (p.His181Arg).
Ambry Genetics	RCV004021559	SCV003677224	uncertain significance	not specified	2022-06-17	criteria provided, single submitter	clinical testing	The c.1904A>G (p.H635R) alteration is located in exon 14 (coding exon 14) of the BIVM-ERCC5 gene. This alteration results from a A to G substitution at nucleotide position 1904, causing the histidine (H) at amino acid position 635 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.