13-51958361-TG-TGG

Position:

• chr13-51958361-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000242839.10(ATP7B):​c.2304_2305insC​(p.Met769HisfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: ATP7B ENST00000242839.10 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: -2.18

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51958361-T-TG is Pathogenic according to our data. Variant chr13-51958361-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 456552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4	c.2304_2305insC	p.Met769HisfsTer26	frameshift_variant	8/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.2304_2305insC	p.Met769HisfsTer26	frameshift_variant	8/21	1	NM_000053.4	ENSP00000242839	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249552 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135390

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000935 AC XY: 68 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74318

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000945

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:17 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 08, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP1-S,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change creates a premature translational stop signal (p.Met769Hisfs*26) 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 (rs780558532, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 15024742, 20517649, 21796144, 22735241, 24897373, 25390358; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 456552). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Feb 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 06, 2024	This variant inserts 1 nucleotide in exon 8 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in many individuals affected with Wilson disease, including in the compound heterozygous or homozygous state (PMID: 8533760, 9311736, 15024742, 16283883, 20517649, 21796144, 22735241, 23551039, 24897373, 25390358, 26253413, 26799313, 28717664, 30702195, 30884209, 31708252, 33804940, 34400371; DOI: 10.1016/j.ymgmr.2022.100861). Lymphoblast cells derived from an individual homozygous for this variant showed loss of copper-stimulated ATPase activity (PMID: 9311736). This variant co-segregated with Wilson disease and demonstrated a recessive inheritance pattern in large families from Romania and Lebanon (PMID: 24897373, 25390358). This variant has been identified in 32/280946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 22, 2023	The ATP7B c.2304dup; p.Met769HisfsTer26 variant (rs137853287), also known as 2299insC or 2304_2305insC, is a recurrent alteration found in patients diagnosed with Wilson disease and is reported to co-segregate with disease (Cocos 2014, Hua 2016, Thomas 1995, Usta 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 456552). It is found in the general population with an overall allele frequency of 0.01% (32/280946 alleles) in the Genome Aggregation Database. This variant causes a frameshift by duplicating a single nucleotide, so it 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: Cocos R et al. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One. 2014 Jun 4;9(6):e98520. PMID: 24897373. 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. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. PMID: 7626145. Usta J et al. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One. 2014 Nov 12;9(11):e109727. PMID: 25390358. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). It is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000456552 / PMID: 7626145). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Met769HisfsX26 variant in ATP7B has been reported in many individuals with Wilson disease (including at least 1 homozygote and 9 compound heterozygotes) and segregated in at least 4 affected relatives (Cocos 2014, Coffey 2013, Mihaylova 2012). It has also been identified in 0.01% (32/280946) of the total chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 769 and leads to a premature termination codon 26 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2017	Variant summary: The ATP7B c.2304dupC (p.Met769Hisfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2336G>A, p.Trp779X; c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. One functional study showed more than 50% decrease in ATPase activity in lymphoblasts a WD homozygote patient (Shah_AJHG_1997). The variant of interest has been found in a large, broad control population, ExAC in 8/120692 control chromosomes at a frequency of 0.0000663, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). This variant has been reported in different cohorts of WD patients (heterozygotes and homozygotes) and is a known common disease variant present in 6% of Croatian patients and 8% Mediterranean populations (Sardinian, continental Italian, Turkish, Albanian)(Figus_AJHG_1995, Ljubic_Genetic Testing and Molecular Biomarkers_2016). In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.2304dup (p.Met769HisfsTer26) in the ATP7B gene has been reported previously in homozygous and compound heterozygous states in multiple individuals with Wilson disease (Weiss KH, et al., 2010, Wang LH, et al., 2011). An experimental study showed this variant caused a more than 50% decrease in ATPase activity in lymphoblasts in a homozygote patient affected with Wilson disease (Shah et al., 1997). The variant has 0.01% allele frequency in gnomAD Exomes. The variant is submitted to ClinVar as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Methionine 769, changes this amino acid to Histidine residue, and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Met769HisfsTer26. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant is also known as c.2299insC or c.2298_2299insC in the literature. This frameshifting variant in exon 8 of 21 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous or homozygous change in multiple unrelated individuals with Wilson disease (PMID: 7626145, 24897373, 25390358). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.011% (32/280946) and thus is presumed to be rare. Based on the available evidence, the c.2304dup (p.Met769HisfsTer26) variant is classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 7626145, 26799313, 34400371, 30291343, 24897373, 27398169, 26819605, 23159873, 28776642, 20517649, 23982005, 28717664, 25390358, 15024742, 30655162, 31708252, 30366773, 32345733, 31980526, 30275481, 31589614, 32005694, 33763395, 34426522, 34240825, 33159804, 18034201, 28855492, 28212618) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	ATP7B: PVS1, PM2, PP4, PS4:Supporting -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2021

The c.2304dupC (p.M769Hfs*26) alteration, located in coding exon 8 of the ATP7B gene, consists of a duplication of C at position 2304, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the ATP7B c.2304dupC alteration was observed in 0.01% (32/280946) of total alleles studied. The c.2304dupC (p.M769Hfs*26) alteration has been reported in multiple unrelated individuals diagnosed with Wilson's disease in both the homozygous and compound heterozygous state (Deguti, 2004; Wang, 2011; Bem, 2013; Dastsooz, 2014; Yuan, 2015; Yu, 2017). The age of onset and the primary manifestation of disease is variable in these patients. A female patient homozygous for the c.2304dupC alteration presented at age 6 with primary liver involvement and Kayser-Fleischer rings (Dastsooz, 2014) while a patient with the c.2304dupC alteration in trans with a missense alteration (p.R919G) presented at age 17 with osseomuscular type Wilson's disease (Yu, 2017). Based on the available evidence, this alteration is classified as pathogenic. -

ATP7B-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The ATP7B c.2304dupC variant is predicted to result in a frameshift and premature protein termination (p.Met769Hisfs*26). This variant has been repeatedly documented to be causative for Wilson disease in the literature (see for example, Shah et al. 1997. PubMed ID: 9311736; Yu et al. 2017. PubMed ID: 28212618; Balashova et al. 2020. PubMed ID: 31708252). In addition, this variant is interpreted as pathogenic in ClinVar by several clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/456552/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in ATP7B are expected to be pathogenic. Based on the collective evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137853287; hg19: chr13-52532497;