Submissions for variant NM_000400.4(ERCC2):c.594+2_594+5del

dbSNP: rs762309206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454337	SCV000538021	likely pathogenic	Trichothiodystrophy 1, photosensitive	2015-12-04	criteria provided, single submitter	clinical testing	The c.594+2_594+5delTGAG splice-donor variant in the ERCC2 gene has not been previously reported. There has been a splice-donor variant in intron 7 of the ERCC2 gene observed in one affected individual with Trichothiodystrophy and was predicted to be a null allele. The affected individual was heterozygous for the splice-donor variant but also harbored a missense variant of unknown significance in the ERCC2 gene (Viprakasit et al., 2001). Although missense variants are a common mechanism for disease, loss of function variants have been reported in individuals affected with Xeroderma Pigmentosum. The c.594+2_594+5delTGAG splice-donor variant is present at a very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc). Computational algorithms predict evolutionary conservation at this locus and a loss of the splice-donor site resulting in intron retention and introduction of a premature termination codon. In summary, this collective evidence supports the provisional classification of the c.594+2_594+5delTGAG variant as Likely Pathogenic
Eurofins Ntd Llc (ga)	RCV000599593	SCV000704022	likely pathogenic	not provided	2016-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000599593	SCV000709929	pathogenic	not provided	2022-08-25	criteria provided, single submitter	clinical testing	Observed in trans with a second ERCC2 variant in an individual with trichothiodystrophy (Viprakasit 2001); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; This variant is associated with the following publications: (PMID: 34426522, 31589614, 29754767, 11734544)
CeGaT Center for Human Genetics Tuebingen	RCV000599593	SCV001151956	likely pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ERCC2: PVS1, PS4:Supporting
Invitae	RCV000599593	SCV001574605	likely pathogenic	not provided	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change affects a splice site in intron 7 of the ERCC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC2 are known to be pathogenic (PMID: 9238033, 11335038, 19085937, 19934020). This variant is present in population databases (rs762309206, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with trichothiodystrophy (PMID: 11734544). ClinVar contains an entry for this variant (Variation ID: 402226). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000454224	SCV002767817	likely pathogenic	Xeroderma pigmentosum, group D	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with xeroderma pigmentosum, group D (MIM#278730). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotides are highly conserved. (SP) 0705 - No comparable canonical splice site variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as likely pathogenic in at least 5 individuals in relation to photosensitive trichothiodystrophy 1 (MIM#601675) and xeroderma pigmentosum, group D (MIM#278730) (ClinVar, HGMD, PMID: 11734544). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_000400.3(ERCC2): c.2047C>T; p.(Arg683Trp)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155181	SCV003845006	pathogenic	Xeroderma pigmentosum	2023-02-20	criteria provided, single submitter	clinical testing	Variant summary: ERCC2 c.594+2_594+5delTGAG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Four predict the variant creates a cryptic 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Punj_2018). The variant allele was found at a frequency of 7.6e-05 in 250738 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (7.6e-05 vs 0.00061), allowing no conclusion about variant significance. c.594+2_594+5delTGAG has been reported in the literature in individuals affected with Xeroderma Pigmentosum or Trichothiodystrophy, Acute lymphoblastic leukemia case, Hodgkin lymphoma (Mixed Cellularity), and Lung cancer (Viprakasit_2001, Punj_2018, Kim_2021, Mukherjee_2022). These data indicate that the variant is very likely to be associated with disease. Six ClinVar submitter (evaluation after 2014) cites this variant as pathogenic (n=1) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003470390	SCV004194620	pathogenic	Cerebrooculofacioskeletal syndrome 2	2023-10-15	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000454224	SCV000538022	likely pathogenic	Xeroderma pigmentosum, group D	2015-12-04	no assertion criteria provided	clinical testing