rs200911496

chr13-51939062-T-Cchr13-51939062-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP5

The NM_000053.4(ATP7B):c.3688A>G(p.Ile1230Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,614,256 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1230L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:10
• Conservation: PhyloP100: 7.97

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000053.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51939062-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1497544.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 13-51939062-T-C is Pathogenic according to our data. Variant chr13-51939062-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 312379.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=10, Pathogenic=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3688A>G	p.Ile1230Val	missense_variant	17/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3688A>G	p.Ile1230Val	missense_variant	17/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000321 AC: 80 AN: 249584 Hom.: 0 AF XY: 0.000362 AC XY: 49 AN XY: 135410

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000600

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000675 AC: 987 AN: 1461890 Hom.: 2 Cov.: 32 AF XY: 0.000671 AC XY: 488 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000834

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74512

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000554 Hom.: 0

Bravo AF: 0.000397

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000473 AC: 4

ExAC AF: 0.000297 AC: 36

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wilson disease Pathogenic:5 Uncertain:5

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Feb 10, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces isoleucine with valine at codon 1230 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 18373411, 23389864; DOI:10.4172/lpma.1000228), intellectual disability (PMID: 28554332), and schizophrenia (PMID: 30556376). This variant has been identified in 96/280998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 19, 2023	This ATP7B missense variant has been reported in individuals with clinical features of Wilson disease, and at least one of these individuals had a second variant in trans that was established to be pathogenic. This variant (rs200911496) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 74/152248 total alleles; 0.05%; no homozygotes). It has been reported in ClinVar (Variation ID 312379). Two bioinformatic tools queried predict that this substitution would be damaging, and the isoleucine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.3688A>G; p.Ile1230Val in ATP7B to be uncertain at this time. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2023	The ATP7B c.3688A>G; p.Ile1230Val variant (rs200911496) is reported in the literature in individuals affected with Wilson disease (Davies 2008, Denoyer 2013, Otto 2016), including in the compound heterozygous state with another pathogenic variant (Denoyer 2013). This variant is reported in ClinVar (Variation ID: 312379), and found in the general population with an overall allele frequency of 0.034% (96/280998 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.801). Additionally, another variant at this codon (c.3689T>C; p.Ile1230Thr) has been reported in the compound heterozygous state in an individual with Wilson disease (Li 2019). Based on available information, the p.Ile1230Val variant is considered likely pathogenic. References: Davies LP et al. New mutations in the Wilson disease gene, ATP7B: implications for molecular testing. Genet Test. 2008 Mar;12(1):139-45. PMID: 18373411. Denoyer Y et al. Neurological Wilson's disease lethal for the son, asymptomatic in the father. Mov Disord. 2013 Mar;28(3):402-3. PMID: 23389864. Li X et al. Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants. Hum Mutat. 2019 May;40(5):552-565. PMID: 30702195. Otto PA et al. Estimation of Allele Frequencies and Population Incidence of Wilson Disease in Brazil. Prensa Med Argent 2016, 102:5. http://dx.doi.org/10.4172/lpma.1000228 -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.3688A>G (p.Ile1230Val) variant has been reported in association with Wilson disease at least two patients in a compound heterozygous state (Davies et al. 2008; Denoyer et al. 2012). One patient was described as being asymptomatic, but showed slightly altered copper metabolism upon further serological and urine testing (Denoyer et al. 2012). This variant was absent from 53 control chromosomes from European individuals and is suggested to be in a well-conserved region (Davies et al. 2008). The p.Ile1230Val variant is reported at a frequency of 0.0005 in the European (Non-Finnish) population of the Exome Aggregation Consortium, including in one individual in a homozygous state. The evidence for this variant is limited. The p.Ile1230Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Wilson disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1230 of the ATP7B protein (p.Ile1230Val). This variant is present in population databases (rs200911496, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of Wilson disease (PMID: 18373411, 23389864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 312379). 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 not expected to disrupt ATP7B protein function with a negative predictive value of 80%. This variant disrupts the p.Ile1230 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30702195; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 11, 2020	Based on the classification scheme VCGS_Germline_v1.3.2, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Wilson disease. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (96 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated hydrolase domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternate change to threonine at the same residue has previously been reported as pathogenic in a patient with Wilson disease. The variant was compound heterozygous and functional studies demonstrated a significant reduction in cell growth (PMID: 30702195). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. The variant has previously been reported as both pathogenic and a VUS, in patients with Wilson disease and in unaffected carriers (ClinVar, HGMD, LOVD, PMID: 18373411, PMID: 23389864, PMID: 30097039, PMID: 30556376). (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 10, 2022	This missense variant replaces isoleucine with valine at codon 1230 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 18373411, 23389864; DOI:10.4172/lpma.1000228), intellectual disability (PMID: 28554332), and schizophrenia (PMID: 30556376). This variant has been identified in 96/280998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 26, 2022	Variant summary: ATP7B c.3688A>G (p.Ile1230Val) results in a conservative amino acid change located in the ATP loop of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 251268 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (0.00032 vs 0.0054), allowing no conclusion about variant significance. c.3688A>G has been reported in the literature as a non-informative genotype (complete genotype not specified) in individuals affected with Wilson Disease (example, Davies_2008, Otto_2016, Sriretnakumar_2018) and one as a secondary carrier genotype in an individual with developmental and/or intellectual delays (example, Bowling_2017). Denoyer_2013 reports the variant to occur in a family in which the proband diagnosed with Wilson Disease was a compound heterozygote for two different variants, namely p.Glu127LysfsX26/p.Gly691Arg and his father who was indicated to be clinically asymptomatic although presenting with a right Kayser-Fleischer ring and altered copper levels was a compound heterozygote for this variant (p.Ile1230Val) and p.Gly691Arg. These report(s) do not provide unequivocal conclusions about association of the variant with Wilson Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely pathogenic, n=4; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: p.Ile1230Val in HGMD. Reported in one publication in patient(s) with Wilson disease (Davies 2008; full text not available). 0.1% in ExAC, including 1 homozygote. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Identified in a patient with Wilson disease (Davies et al., 2008); however, detailed clinical information was not provided; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20465995, 22692182, 32248359, 34426522, 30556376, 30275481, 26752957, 31059521, 28554332, 28050010, 26986070, 30702195, 30019023, 26659599, 30097039, 18373411, 29790872, 28440294, 23389864) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

Davies, 2008; Denoyer, 2013 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D;.;.;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.66	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.81	N;N;N;N;N;.;N
REVEL	Pathogenic	0.80
Sift	Benign	0.055	T;D;D;T;T;.;D
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Polyphen		0.97	D;P;D;P;D;D;D
Vest4		0.74
MVP		0.84
MPC		0.35
ClinPred		0.077	T
GERP RS		5.2
Varity_R		0.32
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs200911496; hg19: chr13-52513198; COSMIC: COSV105028204; COSMIC: COSV105028204;