NM_000053.4:c.2123T>C

Variant names:

• chr13-51958543-A-G
• rs121908000
• NM_000053.4:c.2123T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):​c.2123T>C​(p.Leu708Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L708L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense, splice_region
• Scores: Splicing: ADA: 0.05641
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.51
• Publications: 23 publications found

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]

ATP7B Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in NM_000053.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 13-51958543-A-G is Pathogenic according to our data. Variant chr13-51958543-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 3865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.2123T>C	p.Leu708Pro	missense splice_region	Exon 8 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.2123T>C	p.Leu708Pro	missense splice_region	Exon 9 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.2123T>C	p.Leu708Pro	missense splice_region	Exon 9 of 22	NP_001393441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.2123T>C	p.Leu708Pro	missense splice_region	Exon 8 of 21	ENSP00000242839.5
	ATP7B	ENST00000418097.7	TSL:1	c.2123T>C	p.Leu708Pro	missense splice_region	Exon 8 of 20	ENSP00000393343.2
	ATP7B	ENST00000448424.7	TSL:1	c.1871T>C	p.Leu624Pro	missense splice_region	Exon 6 of 19	ENSP00000416738.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461624 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727130

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111780

Other (OTH) AF: 0.0000166 AC: 1 AN: 60380

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000393 AC: 6 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00000446 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:11

Jul 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATP7B c.2123T>C, p.Leu708Pro variant (rs121908000), has been reported in a homozygous state, or as a compound heterozygote with another pathogenic variant, in patients diagnosed with Wilson disease (Deguti 2004, Garcia-Villarreal 2000, Pena-Quintana 2012, Penon-Portmann 2020, Shah 1997). Patients carrying this variant show decreased serum copper level, increased urine copper excretion, and high hepatic copper content, suggestive of a defect in copper transport (Garcia-Villarreal 2000, Pena-Quintana 2012). This variant is also reported in ClinVar (Variation ID: 3865) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 708 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.851). Based on the above information, the variant is classified as pathogenic. References: Deguti M et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004; 23(4):398. PMID: 15024742 Garcia-Villarreal L et al. High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the Island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology. 2000; 32(6):1329-36. PMID: 11093740 Pena-Quintana L et al. Manifestations and evolution of Wilson disease in pediatric patients carrying ATP7B mutation L708P. J Pediatr Gastroenterol Nutr. 2012; 54(1):48-54. PMID: 32154060 Penon-Portmann M et al. Wilson disease in Costa Rica: Pediatric phenotype and genotype characterization. JIMD Rep. 2020 Feb 6;52(1):55-62. PMID: 32154060 Shah A et al. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Am J Hum Genet. 1997; 61(2):317-28. PMID: 9311736

Mar 31, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ATP7B c.2123T>C (p.Leu708Pro) variant involves the alteration of a conserved nucleotide located in the transmembrane domain of ATB7B. 3/4 in silico tools predict a damaging outcome for this substitution. This variant is absent in 120120 control chromosomes while it was observed in several Wilson Disease patient in either homozygosity or heterozygosity indicating the variant to be pathogenic. Moreover, it is considered to be a founder mutation in the Canary Islands representing about 50% of the WD allele in this population. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 708 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 the homozygous state and compound heterozygous state in many individuals affected with autosomal recessive Wilson disease (PMID: 9311736, 11093740, 15024742, 17897870, 21832955, 23982005), indicating that this variant contributes to disease. This variant was detected in high frequency in several Wilson disease cohorts in the Canary Islands and Brazil (PMID: 11093740, 15024742, 17897870, 21832955). This variant has been identified in 1/31400 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 708 of the ATP7B protein (p.Leu708Pro). This variant is present in population databases (rs121908000, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 9311736, 11093740, 15024742). It is commonly reported in individuals of Canary Islands and Brazil ancestry (PMID: 9311736, 11093740, 15024742). ClinVar contains an entry for this variant (Variation ID: 3865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.

Mar 01, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:3

Nov 11, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 29, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); 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: 22692182, 23982005, 11093740, 21832955, 9311736, 15024742, 32154060)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.74	P
Vest4		0.87
MutPred		0.91		Loss of stability (P = 0.0209)
MVP		0.99
MPC		0.18
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.056
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121908000; hg19: chr13-52532679;