Submissions for variant NM_000124.4(ERCC6):c.3122A>C (p.Gln1041Pro)

gnomAD frequency: 0.00179  dbSNP: rs139007661

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Claritas Genomics	RCV000170382	SCV000222799	uncertain significance	not specified	2014-01-06	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000724216	SCV000226717	uncertain significance	not provided	2018-04-17	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000170382	SCV000247318	uncertain significance	not specified	2014-06-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000358951	SCV000362812	likely benign	COFS syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000266566	SCV000362813	likely benign	Cockayne syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000323987	SCV000362814	likely benign	Macular degeneration	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724216	SCV000572238	likely benign	not provided	2020-12-14	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29602769, 24036952, 28051113)
Fulgent Genetics, Fulgent Genetics	RCV000515412	SCV000611389	uncertain significance	DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; Lung carcinoma; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11	2017-05-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724216	SCV001012454	benign	not provided	2025-01-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000988355	SCV001138043	uncertain significance	DE SANCTIS-CACCHIONE SYNDROME	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000170382	SCV002570499	likely benign	not specified	2022-07-23	criteria provided, single submitter	clinical testing	Variant summary: ERCC6 c.3122A>C (p.Gln1041Pro) results in a non-conservative amino acid change in 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 0.0018 in 251060 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC6 causing Cockayne Syndrome phenotype (0.0016), strongly suggesting that the variant is benign. Although reported in the literature, to our knowledge, no occurrence of c.3122A>C in individuals affected with Cockayne Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002516541	SCV003716651	likely benign	Inborn genetic diseases	2022-01-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000724216	SCV004127660	benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	ERCC6: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000724216	SCV001551323	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ERCC6 p.Gln1041Pro variant was identified in the literature in 1 of 28 proband chromosomes (frequency: 0.036) from individuals with a positive history of cancer (proband had colon cancer) (Castellanos_2017_PMID:28051113). The variant was identified in dbSNP (ID: rs139007661), LOVD 3.0 and ClinVar (classified as benign by Invitae, likely benign by Illumina and uncertain significance by Claritas Genomics, Genetics Services Laboratory University of Chicago, Fulgent Genetics, EGL Genetic Diagnostics and GeneDx). The variant was identified in control databases in 492 of 282474 chromosomes (1 homozygous) at a frequency of 0.001742 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: Latino in 102 of 35408 chromosomes (freq: 0.002881), Other in 20 of 7200 chromosomes (freq: 0.002778), European (non-Finnish) in 317 of 128972 chromosomes (freq: 0.002458), Ashkenazi Jewish in 22 of 10362 chromosomes (freq: 0.002123), European (Finnish) in 15 of 25090 chromosomes (freq: 0.000598), African in 13 of 24904 chromosomes (freq: 0.000522), South Asian in 3 of 30588 chromosomes (freq: 0.000098), but was not observed in the East Asian population. The p.Gln1041 residue is not conserved in mammals and four out of five 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. This variant is classified as a variant of uncertain significance.