Submissions for variant NM_000123.4(ERCC5):c.2751del (p.Lys917fs)

dbSNP: rs752661599

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194154	SCV001363456	pathogenic	Xeroderma pigmentosum	2019-10-21	criteria provided, single submitter	clinical testing	Variant summary: ERCC5 c.2751delA (p.Lys917AsnfsX65) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248226 control chromosomes (gnomAD). c.2751delA has been reported in the literature in a compound heterozygous individual affected with Xeroderma pigmentosum (Lalle_2002). These data indicate that the variant is likely to be associated with disease. In functional studies, the cells transfected with the variant were highly UV sensitive compared to control cells (Lalle_2002).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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003556040	SCV004296520	pathogenic	not provided	2023-07-19	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal is associated with altered splicing resulting in multiple RNA products (PMID: 11841555). Experimental studies have shown that this premature translational stop signal affects ERCC5 function (PMID: 11841555). ClinVar contains an entry for this variant (Variation ID: 16576). This variant is also known as K917fs962fsX1186. This premature translational stop signal has been observed in individuals with clinical features of xeroderma pigmentosum (PMID: 11841555; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys917Asnfs*65) in the ERCC5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 270 amino acid(s) of the ERCC5 protein.
Neuberg Centre For Genomic Medicine, NCGM	RCV000018044	SCV005061212	pathogenic	Xeroderma pigmentosum, group G		criteria provided, single submitter	clinical testing	The frameshift variant c.2751del (p.Lys917AsnfsTer65) in the ERCC5 gene has been reported previously in a heterozygous state in individuals affected with xeroderma pigmentosum (Drury et al., 2014; Lalle et al., 2022). The p.Lys917AsnfsTer65 variant is absent in 1000 Genomes. It has been submitted to ClinVar as Pathogenic. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000018044	SCV000038323	pathogenic	Xeroderma pigmentosum, group G	2002-02-01	no assertion criteria provided	literature only