Submissions for variant NM_000053.4(ATP7B):c.314C>A (p.Ser105Ter)

dbSNP: rs753236073

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169629	SCV000221158	likely pathogenic	Wilson disease	2015-02-27	criteria provided, single submitter	literature only
GeneDx	RCV000293037	SCV000329798	pathogenic	not provided	2016-02-28	criteria provided, single submitter	clinical testing	The S105X variant in the S105X gene has been reported previously in a Hong Kong Chinese patient with Wilson disease who was compound heterozygous for the S105X variant and another loss-of-function variant (Lam et al., 2006; Mak et al., 2008). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S105X variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret S105X as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169629	SCV000694438	pathogenic	Wilson disease	2016-04-25	criteria provided, single submitter	clinical testing	Variant summary: The variant c.314C>A leads to a nonsense mutation resulting in a stop codon at amino acid position 105 in the 1465 amino acid long ATP7B protein. This variant is therefore predicted to lead to a truncated or absent protein. Mutation Taster predicts disease-causing outcome for this substitution. It was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing ATP7B allele (0.54%). The variant was reported in several Wilson disease patients mainly from China, including compound heterozygosity with pathogenic/potentially pathogenic ATP7B variants strongly indicating a pathogenic outcome. One reputable database (HGMD) classifies the variant as pathogenic and one clinical diagnostic center also classifies it as Likely Pathogenic in ClinVar. Considering all evidence, the variant has been classified as a Disease Variant or Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169629	SCV000883441	pathogenic	Wilson disease	2019-05-14	criteria provided, single submitter	clinical testing	The ATP7B c.314C>A; p.Ser105Ter variant (rs753236073) is reported in the literature in the compound heterozygous state in individuals affected with Wilson disease (Genschel 2000, Huong 2018, Mak 2008, Wang 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 189193), and is only observed twice in the Genome Aggregation Database general population database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Genschel J et al. Three novel mutations, c314C>A, C778insC, and c1285+2T>A, in exon 2 of the Wilson disease gene. Hum Mutat. 2000; 16(3):278. Huong NTM et al. Three novel mutations in the ATP7B gene of unrelated Vietnamese patients with Wilson disease. BMC Med Genet. 2018 Jun 18;19(1):104. Mak C et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008; 53(1):55-63. Wang L et al. Mutation analysis of 73 southern Chinese Wilson's disease patients: identification of 10 novel mutations and its clinical correlation. J Hum Genet. 2011; 56(9):660-5.
Invitae	RCV000169629	SCV000935466	pathogenic	Wilson disease	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser105*) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs753236073, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 16510432, 21796144, 29914392). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 189193). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169629	SCV001977407	pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000293037	SCV002525832	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing	PM2, PVS1
Baylor Genetics	RCV000169629	SCV004216394	pathogenic	Wilson disease	2023-06-22	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169629	SCV002087908	pathogenic	Wilson disease	2020-12-28	no assertion criteria provided	clinical testing