ClinVar Miner

Submissions for variant NM_000124.4(ERCC6):c.1009A>T (p.Lys337Ter) (rs1198241866)

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Total submissions: 3
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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 B 2017-02-09 criteria provided, single submitter clinical testing
Invitae RCV000809201 SCV000949344 pathogenic not provided 2018-08-03 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Cockayne syndrome (PMID: 1339317). Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 9443879, 18628313). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449817 SCV001653117 pathogenic Cockayne syndrome B 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.

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