NM_000053.4(ATP7B):c.3434C>G (p.Ser1145Cys) AND Wilson disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003104835.4

Allele description [Variation Report for NM_000053.4(ATP7B):c.3434C>G (p.Ser1145Cys)]

NM_000053.4(ATP7B):c.3434C>G (p.Ser1145Cys)

Gene:

ATP7B:ATPase copper transporting beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q14.3

Genomic location:

Preferred name:

NM_000053.4(ATP7B):c.3434C>G (p.Ser1145Cys)

HGVS:

NC_000013.11:g.51941203G>C
NG_008806.1:g.75292C>G
NM_000053.4:c.3434C>GMANE SELECT
NM_001005918.3:c.2813C>G
NM_001243182.2:c.3101C>G
NM_001330578.2:c.3200C>G
NM_001330579.2:c.3182C>G
NM_001406511.1:c.3434C>G
NM_001406512.1:c.3434C>G
NM_001406513.1:c.3428C>G
NM_001406514.1:c.3401C>G
NM_001406515.1:c.3380C>G
NM_001406516.1:c.3380C>G
NM_001406517.1:c.3338C>G
NM_001406518.1:c.3338C>G
NM_001406519.1:c.3299C>G
NM_001406520.1:c.3290C>G
NM_001406521.1:c.3290C>G
NM_001406522.1:c.3290C>G
NM_001406523.1:c.3251C>G
NM_001406524.1:c.3257C>G
NM_001406525.1:c.3239C>G
NM_001406526.1:c.3434C>G
NM_001406527.1:c.3200C>G
NM_001406528.1:c.3200C>G
NM_001406530.1:c.3194C>G
NM_001406531.1:c.3182C>G
NM_001406532.1:c.3182C>G
NM_001406534.1:c.3146C>G
NM_001406535.1:c.3104C>G
NM_001406536.1:c.3104C>G
NM_001406537.1:c.3095C>G
NM_001406539.1:c.3005C>G
NM_001406540.1:c.2987C>G
NM_001406541.1:c.2948C>G
NM_001406542.1:c.2948C>G
NM_001406544.1:c.2852C>G
NM_001406545.1:c.2786C>G
NM_001406546.1:c.2753C>G
NM_001406547.1:c.2591C>G
NM_001406548.1:c.2144C>G
NP_000044.2:p.Ser1145Cys
NP_001005918.1:p.Ser938Cys
NP_001230111.1:p.Ser1034Cys
NP_001317507.1:p.Ser1067Cys
NP_001317508.1:p.Ser1061Cys
NP_001393440.1:p.Ser1145Cys
NP_001393441.1:p.Ser1145Cys
NP_001393442.1:p.Ser1143Cys
NP_001393443.1:p.Ser1134Cys
NP_001393444.1:p.Ser1127Cys
NP_001393445.1:p.Ser1127Cys
NP_001393446.1:p.Ser1113Cys
NP_001393447.1:p.Ser1113Cys
NP_001393448.1:p.Ser1100Cys
NP_001393449.1:p.Ser1097Cys
NP_001393450.1:p.Ser1097Cys
NP_001393451.1:p.Ser1097Cys
NP_001393452.1:p.Ser1084Cys
NP_001393453.1:p.Ser1086Cys
NP_001393454.1:p.Ser1080Cys
NP_001393455.1:p.Ser1145Cys
NP_001393456.1:p.Ser1067Cys
NP_001393457.1:p.Ser1067Cys
NP_001393459.1:p.Ser1065Cys
NP_001393460.1:p.Ser1061Cys
NP_001393461.1:p.Ser1061Cys
NP_001393463.1:p.Ser1049Cys
NP_001393464.1:p.Ser1035Cys
NP_001393465.1:p.Ser1035Cys
NP_001393466.1:p.Ser1032Cys
NP_001393468.1:p.Ser1002Cys
NP_001393469.1:p.Ser996Cys
NP_001393470.1:p.Ser983Cys
NP_001393471.1:p.Ser983Cys
NP_001393473.1:p.Ser951Cys
NP_001393474.1:p.Ser929Cys
NP_001393475.1:p.Ser918Cys
NP_001393476.1:p.Ser864Cys
NP_001393477.1:p.Ser715Cys
NC_000013.10:g.52515339G>C

Protein change:

S1002C

Molecular consequence:

NM_000053.4:c.3434C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.2813C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.3101C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.3200C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.3182C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406511.1:c.3434C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406512.1:c.3434C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406513.1:c.3428C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406514.1:c.3401C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406515.1:c.3380C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406516.1:c.3380C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406517.1:c.3338C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406518.1:c.3338C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406519.1:c.3299C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406520.1:c.3290C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406521.1:c.3290C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406522.1:c.3290C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406523.1:c.3251C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406524.1:c.3257C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406525.1:c.3239C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406526.1:c.3434C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406527.1:c.3200C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406528.1:c.3200C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406530.1:c.3194C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406531.1:c.3182C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406532.1:c.3182C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406534.1:c.3146C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406535.1:c.3104C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406536.1:c.3104C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406537.1:c.3095C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406539.1:c.3005C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406540.1:c.2987C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406541.1:c.2948C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406542.1:c.2948C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406544.1:c.2852C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406545.1:c.2786C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406546.1:c.2753C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406547.1:c.2591C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406548.1:c.2144C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Wilson disease (WND)
Synonyms:: Wilson's disease; Hepatolenticular degeneration
Identifiers:: MONDO: MONDO:0010200; MedGen: C0019202; Orphanet: 905; OMIM: 277900

Recent activity

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SNX18P25 sorting nexin 18 pseudogene 25 [Homo sapiens]
SNX18P25 sorting nexin 18 pseudogene 25 [Homo sapiens]
Gene ID:100419005

Gene
SNX18P25 AND (alive[prop]) (1)
Gene
PDZ and LIM domain protein 7 isoform 4 [Homo sapiens]
PDZ and LIM domain protein 7 isoform 4 [Homo sapiens]
gi|47157328|ref|NP_998801.1|

Protein
PREDICTED: Morus notabilis uncharacterized LOC21409753 (LOC21409753), mRNA
PREDICTED: Morus notabilis uncharacterized LOC21409753 (LOC21409753), mRNA
gi|1350188291|ref|XM_010110629.2|

Nucleotide
adenine nucleotide translocase lysine N-methyltransferase isoform 2 [Mus musculu...
adenine nucleotide translocase lysine N-methyltransferase isoform 2 [Mus musculus]
gi|553726989|ref|NP_001272911.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003783214	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005042711	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003783214

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 1, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005042711

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV003783214.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1145 of the ATP7B protein (p.Ser1145Cys). This variant is present in population databases (rs754759064, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ATP7B-related conditions. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005042711.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The missense variant c.3434C>G p.Ser1145Cys in the ATP7B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.003% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Serine at position 1145 is changed to a Cysteine changing protein sequence and it might alter its composition and physico- chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser1145Cys in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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