ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.2647G>A (p.Glu883Lys) (rs201652412)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000864380 SCV001005171 likely benign Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia, complementation group Q 2020-11-25 criteria provided, single submitter clinical testing
Mendelics RCV000989536 SCV001139956 likely benign Xeroderma pigmentosum, group F 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000989536 SCV001275988 likely benign Xeroderma pigmentosum, group F 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358163 SCV001553829 likely benign not provided no assertion criteria provided clinical testing The ERCC4 p.Glu883Lys variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs201652412) and in control databases in 134 of 268246 chromosomes (2 homozygous) at a frequency of 0.0004995 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 90 of 30526 chromosomes (freq: 0.002948), Other in 5 of 6702 chromosomes (freq: 0.000746), Ashkenazi Jewish in 6 of 9858 chromosomes (freq: 0.000609), European (non-Finnish) in 31 of 118102 chromosomes (freq: 0.000263) and Latino in 2 of 35108 chromosomes (freq: 0.000057), but was not observed in the African, East Asian, or European (Finnish) populations. The p.Glu883 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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