Submissions for variant NM_000400.4(ERCC2):c.1361TCA[2] (p.Ile456del)

dbSNP: rs750123656

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761139	SCV000891055	likely pathogenic	Craniopharyngioma	2017-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226381	SCV003922651	likely pathogenic	Xeroderma pigmentosum	2023-03-21	criteria provided, single submitter	clinical testing	Variant summary: ERCC2 c.1367_1369delTCA (p.Ile456del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes (gnomAD). c.1367_1369delTCA has been reported in the literature in individuals affected with Xeroderma Pigmentosum (example: Ueda_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Ueda_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003465681	SCV004194667	likely pathogenic	Cerebrooculofacioskeletal syndrome 2	2023-06-10	criteria provided, single submitter	clinical testing
Invitae	RCV003558558	SCV004298413	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	This variant, c.1367_1369del, results in the deletion of 1 amino acid(s) of the ERCC2 protein (p.Ile456del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750123656, gnomAD 0.007%). This variant has been observed in individual(s) with xeroderma pigmentosum (PMID: 19934020). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as I455del. ClinVar contains an entry for this variant (Variation ID: 620626). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ERCC2 function (PMID: 19934020). For these reasons, this variant has been classified as Pathogenic.