rs121907997

Positions:

• chr13-51958369-G-A
• chr13-51958369-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2297C>T​(p.Thr766Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T766R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.94

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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51958369-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 13-51958369-G-A is Pathogenic according to our data. Variant chr13-51958369-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958369-G-A is described in Lovd as [Pathogenic]. Variant chr13-51958369-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2297C>T	p.Thr766Met	missense_variant	8/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2297C>T	p.Thr766Met	missense_variant	8/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249558 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 04, 2020	Variant summary: ATP7B c.2297C>T (p.Thr766Met) results in a non-conservative amino acid change located in the Transmembrane domain 4 (Dong 2016) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250922 control chromosomes. c.2297C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Cox_2005, Mukherjee_2014, Dong_2016, Pham_2017, Shim_2018, Ferenci_2019, Singh_2019). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. In addition, p.Thr766Arg has been reported to associate with Wilson Disease. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 766 of the ATP7B protein (p.Thr766Met). This variant is present in population databases (rs121907997, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 16088907, 24094725, 26483271, 27022412, 29321352, 29930488, 31059521, 33763395). 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: 633064). 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%. This variant disrupts the p.Thr766 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15557537, 21956287). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces threonine with methionine at codon 766 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 observed in individuals affected with autosomal recessive Wilson disease, including in the compound heterozygous and homozygous states (PMID: 16088907, 24094725, 26483271, 27022412, 29321352, 29930488, 30232804, 31059521, 33763395, 34240825). A different variant affecting the same codon, c.2297C>G (p.Thr766Arg), is considered to be disease-causing (ClinVar variation ID: 3861), suggesting that Thr at this position is important for the protein function. This variant has been identified in 11/280966 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 15, 2020	The ATP7B c.2297C>T; p.Thr766Met variant (rs121907997) is reported in the medical literature in several individuals with a clinical diagnosis of Wilson disease (Cox 2005, Dong 2016, Mukherjee 2014). The variant is reported in the ClinVar database (Variation ID: 633064) and is listed in the general population with an overall allele frequency of 0.0039% (11/280,966 alleles) in the Genome Aggregation Database. The threonine at codon 766 is highly conserved, occurs in the highly conserved transmembrane domain, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.2297C>G; p.Thr766Arg) has been reported in individuals with Wilson disease (Pendlebury 2004, Wilcox 2011). Based on available information, this variant is considered to be likely pathogenic. References: Cox DW et al. Twenty-four Novel Mutations in Wilson Disease Patients of Predominantly European Ancestry. Hum Mutat. 2005 Sep;26(3):280. Dong Y et al. Spectrum and Classification of ATP7B Variants in a Large Cohort of Chinese Patients With Wilson's Disease Guides Genetic Diagnosis. Theranostics. 2016 Mar 3;6(5):638-49. Mukherjee S et al. Genetic Defects in Indian Wilson Disease Patients and Genotype-Phenotype Correlation. Parkinsonism Relat Disord. 2014 Jan;20(1):75-81 Pendlebury ST et al. Strokelike Presentation of Wilson Disease With Homozygosity for a Novel T766R Mutation. Neurology. 2004 Nov 23;63(10):1982-3. Wilcox RA et al. Whispering Dysphonia in an Australian Family (DYT4): A Clinical and Genetic Reappraisal. Mov Disord. 2011 Nov;26(13):2404-8. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	ATP7B: PM3:Strong, PM2, PM5, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.6	D;D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.93
MutPred		0.88		Loss of phosphorylation at T762 (P = 0.1135);.;.;Loss of phosphorylation at T762 (P = 0.1135);
MVP		0.98
MPC		0.38
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.84

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: rs121907997; hg19: chr13-52532505;