ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.442C>T (p.His148Tyr)

gnomAD frequency: 0.00004  dbSNP: rs201382232
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001926551 SCV002198514 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 148 of the ERCC2 protein (p.His148Tyr). This variant is present in population databases (rs201382232, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ERCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1423195). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222744 SCV002500201 uncertain significance not specified 2022-03-08 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.442C>T (p.His148Tyr) results in a conservative amino acid change located in the Helicase-like, DEXD box c2 type of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250800 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (6.8e-05 vs 0.00061), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.442C>T in individuals affected with Xeroderma Pigmentosum and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV001926551 SCV005194680 uncertain significance not provided criteria provided, single submitter not provided
3billion RCV004728951 SCV005328613 likely benign Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2024-09-20 criteria provided, single submitter clinical testing The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.
Fulgent Genetics, Fulgent Genetics RCV004728951 SCV005648425 uncertain significance Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2024-02-09 criteria provided, single submitter clinical testing

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