Submissions for variant NM_000053.4(ATP7B):c.3809A>G (p.Asn1270Ser)

gnomAD frequency: 0.00003  dbSNP: rs121907990

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000004063	SCV000192352	pathogenic	Wilson disease	2013-02-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004063	SCV000626859	pathogenic	Wilson disease	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1270 of the ATP7B protein (p.Asn1270Ser). This variant is present in population databases (rs121907990, gnomAD 0.08%). This missense change has been observed in individuals with Wilson disease (PMID: 20485189, 26269689, 27398169). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3859). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 9654149, 22240481). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000595271	SCV000700721	pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004063	SCV000918603	pathogenic	Wilson disease	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: ATP7B c.3809A>G (p.Asn1270Ser) results in a conservative amino acid change in 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 0.00015 in 120980 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.3809A>G has been reported in the literature in numerous individuals affected with Wilson Disease as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence on the variant and showed that copper uptake and transport are both defective (Huster_2012). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000004063	SCV001157792	pathogenic	Wilson disease	2022-12-22	criteria provided, single submitter	clinical testing	The ATP7B c.3809A>G; p.Asn1270Ser variant (rs121907990) is reported in the literature in numerous individuals affected with Wilson disease (Abuduxikuer 2015, Barada 2010, Daneshjoo 2018, Guggilla 2015, Hua 2016, Tanzi 1993, Todorov 2005). This variant has been reported to cosegregate with disease in families, both in the homozygous state (Barada 2010, Tanzi 1993) and in trans to another pathogenic variant (Daneshjoo 2018). The asparagine at codon 1270 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.896). Biochemical analyses indicate this variant has severely reduced copper transport activity (Huster 2012), and it fails to rescue growth defects of mutant yeast to the extent of wildtype protein (Iida 1998). Additionally, other variants at this codon (p.Asn1270Asp, p.Asn1270Ile) have been reported in Wilson disease patients (Nemeth 2016, Tuan Pham 2017). The p.Asn1270Ser variant is reported in ClinVar (Variation ID: 3859), and is found in the general population with an overall allele frequency of 0.020% (55/280972 alleles, including a single homozygote) in the Genome Aggregation Database. Based on available information, the p.Asn1270Ser variant is considered to be pathogenic. References: Abuduxikuer K et al. Wilson disease with hepatic presentation in an eight-month-old boy. World J Gastroenterol. 2015 Aug 7;21(29):8981-4. PMID: 26269689. Barada K et al. Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. J Clin Gastroenterol. 2010 Jul;44(6):432-9. PMID: 20485189. Daneshjoo O and Garshasbi M. Novel compound heterozygote mutations in the ATP7B gene in an Iranian family with Wilson disease: a case report. J Med Case Rep. 2018 Mar 15;12(1):68. PMID: 29540233. Guggilla SR et al. Spectrum of mutations in the ATP binding domain of ATP7B gene of Wilson Disease in a regional Indian cohort. Gene. 2015 Sep 10;569(1):83-7. PMID: 25982861. Hua R et al. Mutational analysis of ATP7B in Chinese Wilson disease patients. Am J Transl Res. 2016 Jun 15;8(6):2851-61. PMID: 27398169. Huster D et al. Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology. 2012 Apr;142(4):947-956.e5. PMID: 22240481. Iida M et al. Analysis of functional domains of Wilson disease protein (ATP7B) in Saccharomyces cerevisiae. FEBS Lett. 1998 May 29;428(3):281-5. PMID: 9654149. Nemeth D et al. Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease. Gastroenterol Res Pract. 2016;2016:4548039. PMID: 26819605. Tanzi RE et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet. 1993 Dec;5(4):344-50. PMID: 8298641. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. PMID: 16207219. Tuan Pham LA et al. Genetic analysis of 55 northern Vietnamese patients with Wilson disease: seven novel mutations in ATP7B. J Genet. 2017 Dec;96(6):933-939. PMID: 29321352.
Myriad Genetics, Inc.	RCV000004063	SCV001194119	pathogenic	Wilson disease	2020-01-03	criteria provided, single submitter	clinical testing	NM_000053.3(ATP7B):c.3809A>G(N1270S) is classified as pathogenic in the context of Wilson Disease. Sources cited for classification include the following: PMID 23518715, 12544487, 22240481, 10790207, 9452121, 9829905, 19419418, 9311736, 7626145 and 9654149. Classification of NM_000053.3(ATP7B):c.3809A>G(N1270S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV000595271	SCV001247791	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	ATP7B: PM2, PM3, PM5, PP1, PP4, PS3:Supporting, PS4:Supporting
Mayo Clinic Laboratories, Mayo Clinic	RCV000595271	SCV001713633	pathogenic	not provided	2022-03-18	criteria provided, single submitter	clinical testing	PP3, PP4, PP5, PM2, PS3, PS4_moderate
Fulgent Genetics, Fulgent Genetics	RCV000004063	SCV001752571	pathogenic	Wilson disease	2022-01-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000004063	SCV001810290	pathogenic	Wilson disease	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004063	SCV002024364	pathogenic	Wilson disease	2023-08-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000595271	SCV002558357	pathogenic	not provided	2022-04-21	criteria provided, single submitter	clinical testing	Published functional studies indicate that this variant leads to hyperphosphorylation and affects copper transport, supporting a damaging effect (Iida et al., 1998; Huster et al., 2012); 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: 24253677, 20485189, 22240481, 9654149, 29540233, 8298641, 32154060, 30655162, 23518715, 30275481, 25637381, 22692182, 25982861, 26269689, 27398169, 10194254, 9829905, 19419418, 7626145, 9452121, 12544487, 10790207, 9311736, 30558096, 31708252, 34324271, 31589614, 34426522, 34240825, 34470610, Huong2022[article], 35222532, 33879678, Rosa2022[article], 34002136, 35395623)
Ambry Genetics	RCV002354147	SCV002620184	pathogenic	Inborn genetic diseases	2017-08-03	criteria provided, single submitter	clinical testing	The p.N1270S pathogenic mutation (also known as c.3809A>G), located in coding exon 18 of the ATP7B gene, results from an A to G substitution at nucleotide position 3809. The asparagine at codon 1270 is replaced by serine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with Wilson disease, including several homozygous individuals (Yoo HW. Genet. Med. 2002;4:43S-48S; Deguti MM et al. Hum. Mutat., 2004 Apr;23:398; Barada K et al. J. Clin. Gastroenterol., 2010 Jul;44:432-9). When expressed in Sf9 cells, this mutation demonstrated impaired chloride transport and hyperphosphorylation (Huster D et al. Gastroenterology, 2012 Apr;142:947-956.e5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000004063	SCV003932614	pathogenic	Wilson disease	2023-06-14	criteria provided, single submitter	clinical testing	A homozygous missense variant in exon 18 of the ATP7B gene that results in the amino acid substitution of Serine for Asparagine at codon 1270 (p.Asn1270Ser) was detected. The p.Asn1270Ser variant has not been reported in the 1000 genomes databases and has a minor allele frequency of 0.04%, 0.02% and 0.03% in the gnomAD (v3.1), gnomdAD (v2) and topmed databases respectively. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Baylor Genetics	RCV000004063	SCV004216259	pathogenic	Wilson disease	2024-03-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904803	SCV004726765	pathogenic	ATP7B-related disorder	2023-11-03	criteria provided, single submitter	clinical testing	The ATP7B c.3809A>G variant is predicted to result in the amino acid substitution p.Asn1270Ser. This variant has been repeatedly documented as causative for Wilson disease (Tanzi et al. 1993. PubMed ID: 8298641; Yoo et al. 2002. PubMed ID: 12544487; Zhang et al. 2013. PubMed ID: 23235335). Functional studies suggest that this variant alters normal protein function (Table S1, Schushan et al. 2012. PubMed ID: 22692182). In summary, we interpret this variant as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004063	SCV004847782	pathogenic	Wilson disease	2020-06-11	criteria provided, single submitter	clinical testing	The p.Asn1270Ser variant in ATP7B has been identified in >50 probands across multiple ethnic groups with Wilson disease, including at least 4 homozygotes and >15 compound heterozygotes, and has segregated in at least 4 affected siblings (Abuduxikuer 2015, Barada2010, Bost 2012, Chen 2019, Coffey 2013, Daneshjoo 2018, Deguti 2004, Dong 2016, Guggilla 2015, Hua 2016, Kuppala 2009, Li 2013, Okada 2000, Shah 1997, Wan 2010, Yoo 2002, Zali 2011). This variant has also been identified in 0.08% (30/35376) of Latino chromosomes, including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency given an estimated prevalence of 1/30000 for Wilson disease. In vitro functional studies suggest that the variant may impact protein function (Huster 2012, Lida 1998), and computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PP3, PP4, PS3_Supporting.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000004063	SCV005038887	uncertain significance	Wilson disease	2024-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000004063	SCV000024229	pathogenic	Wilson disease	2009-04-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000004063	SCV000190069	pathogenic	Wilson disease	2014-06-01	no assertion criteria provided	research
Natera, Inc.	RCV000004063	SCV001455581	pathogenic	Wilson disease	2020-09-16	no assertion criteria provided	clinical testing