ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.1009A>T (p.Lys337Ter)

dbSNP: rs1198241866
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665546 SCV000789688 likely pathogenic DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2 2017-02-09 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000809201 SCV000949344 pathogenic not provided 2024-06-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys337*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 1339317). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550722). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001449817 SCV001653117 pathogenic Cockayne syndrome type 2 2021-02-22 criteria provided, single submitter clinical testing The p.Lys337X variant in ERCC6 has been reported in a compound heterozygous state in an individual with Cockayne syndrome, who carried a second pathogenic variant in ERCC6 (Troelstra 1992 PMID: 1339317, Schmickel 1977 PMID: 887325). It has also been identified in 1/113716 European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID 550722). This nonsense variant leads to a premature termination codon at position 337, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC6 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. An animal model in ERCC6 has shown that a similar variant causes some features of Cockayne Syndrome including photosensitivity, but only mild deficits in growth and neurologic function (van Der Horst 1997 PMID: 9150142). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP criteria applied: PVS1, PM2_Suporting, PM3, PS3_Moderate.
Fulgent Genetics, Fulgent Genetics RCV005046853 SCV005681625 pathogenic DE SANCTIS-CACCHIONE SYNDROME; Cerebrooculofacioskeletal syndrome 1; Cockayne syndrome type 2; UV-sensitive syndrome 1; Age related macular degeneration 5; Premature ovarian failure 11; Lung cancer 2024-01-19 criteria provided, single submitter clinical testing

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