Submissions for variant NM_000053.4(ATP7B):c.3646G>A (p.Val1216Met)

gnomAD frequency: 0.00006  dbSNP: rs776280797

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169211	SCV000220467	likely pathogenic	Wilson disease	2014-07-02	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000725176	SCV000334638	likely pathogenic	not provided	2015-08-28	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169211	SCV000894014	likely pathogenic	Wilson disease	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000169211	SCV001158551	likely pathogenic	Wilson disease	2019-06-13	criteria provided, single submitter	clinical testing	The ATP7B c.3646G>A; p.Val1216Met variant (rs776280797) is reported in the literature in multiple individuals affected with Wilson disease (Haas 1999, Liu 2004, Loudianos 1998, Mak 2008, Margarit 2005, Qian 2019). Multiple affected individuals with this variant were also found to carry an additional pathogenic variant (Liu 2004, Margarit 2005, Qian 2019). The p.Val1216Met variant is found in the general population with the low overall allele frequency of 0.01% (24/280998 alleles) in the Genome Aggregation Database, and it is reported as likely pathogenic by multiple laboratories in ClinVar (Variation ID: 188859). The valine at codon 1216 is highly conserved, occurs in the functionally important ATP-binding loop (Loudianos 1998, Mak 2008), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Haas R et al. Mutation analysis in patients with Wilson disease: identification of 4 novel mutations. Mutation in brief no. 250. Online. Hum Mutat. 1999;14(1):88. Liu XQ et al. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol. 2004 Feb 15;10(4):590-3. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Mak CM 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. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649.
Baylor Genetics	RCV000169211	SCV001163728	pathogenic	Wilson disease	2024-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV000169211	SCV001234718	pathogenic	Wilson disease	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1216 of the ATP7B protein (p.Val1216Met). This variant is present in population databases (rs776280797, gnomAD 0.07%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10447265, 14966923, 15952988, 26253413). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188859). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000169211	SCV001977244	likely pathogenic	Wilson disease	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169211	SCV002766240	pathogenic	Wilson disease	2022-11-17	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3646G>A (p.Val1216Met) results in a conservative amino acid change located in the ATP-binding domain (Yuan_2015, Dong_2016) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 249592 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (8.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3646G>A has been reported in the literature as a biallelic genotype and as an uninformative genotype (second allele not reported/specified) in multiple individuals affected with Wilson Disease (e.g. Loudianos_1998, Haas_1999, Lee_2000, Margarit_2005, Park_2007, Yuan_2015, Balashova_2020) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=1) or likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000725176	SCV004036652	likely pathogenic	not provided	2023-03-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18034201, 21219664, 31589614, 29637721, 18371106, 22692182, 30655162, 27022412, 34240825, 21645214, 17876883, 17587212, 20931554, 11043508, 8298641, 35220961, 26782526, 32618023, 9671269, 31708252, 30275481, 34324271, 35470480, 10447265, 14966923, 31172689, 26253413, 22677543, 30884209, 34620762, 27982432, 15952988)
All of Us Research Program, National Institutes of Health	RCV000169211	SCV004828330	pathogenic	Wilson disease	2024-01-11	criteria provided, single submitter	clinical testing	Well-established functional studies suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 29637721, 30133932, 24253677). This variant has been reported in multiple individuals with Wilson disease and is one of the five most common pathogenic variants in the Chinese population (PMID: 35220961, 30884209, 26253413, 32618023, 26782526, 34324271, 31708252, 17876883, 34470610). This variant is located in a well-established functional domain of the protein where other pathogenic or likely pathogenic variants have been described (PMID: 35296237, 14966923). This gene has fewer missense variants in the general population than expected, which suggests that this gene is intolerant to missense variation.