NM_000053.4(ATP7B):c.1142T>G (p.Ile381Ser) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 30, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003331123.1

Allele description [Variation Report for NM_000053.4(ATP7B):c.1142T>G (p.Ile381Ser)]

NM_000053.4(ATP7B):c.1142T>G (p.Ile381Ser)

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.1142T>G (p.Ile381Ser)

HGVS:

NC_000013.11:g.51974078A>C
NG_008806.1:g.42417T>G
NM_000053.4:c.1142T>GMANE SELECT
NM_001005918.3:c.1142T>G
NM_001243182.2:c.809T>G
NM_001330578.2:c.1142T>G
NM_001330579.2:c.1142T>G
NP_000044.2:p.Ile381Ser
NP_001005918.1:p.Ile381Ser
NP_001230111.1:p.Ile270Ser
NP_001317507.1:p.Ile381Ser
NP_001317508.1:p.Ile381Ser
NC_000013.10:g.52548214A>C
NM_000053.3:c.1142T>G

Protein change:

I270S

Links:

dbSNP: rs766943890

NCBI 1000 Genomes Browser:

rs766943890

Molecular consequence:

NM_000053.4:c.1142T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001005918.3:c.1142T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001243182.2:c.809T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330578.2:c.1142T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001330579.2:c.1142T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004037737	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Aug 30, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23518715, 36096368 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004037737

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Aug 30, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A genetic study of Wilson's disease in the United Kingdom.

Coffey AJ, Durkie M, Hague S, McLay K, Emmerson J, Lo C, Klaffke S, Joyce CJ, Dhawan A, Hadzic N, Mieli-Vergani G, Kirk R, Elizabeth Allen K, Nicholl D, Wong S, Griffiths W, Smithson S, Giffin N, Taha A, Connolly S, Gillett GT, Tanner S, et al.

Brain. 2013 May;136(Pt 5):1476-87. doi: 10.1093/brain/awt035. Epub 2013 Mar 21.

PubMed [citation]

PMID:: 23518715
PMCID:: PMC3634195

ATP7B Genotype and Chronic Liver Disease Treatment Outcomes in Wilson Disease: Worse Survival With Loss-of-Function Variants.

Nayagam JS, Jeyaraj R, Foskett P, Dhawan A, Ala A, Joshi D, Bomford A, Thompson RJ.

Clin Gastroenterol Hepatol. 2023 May;21(5):1323-1329.e4. doi: 10.1016/j.cgh.2022.08.041. Epub 2022 Sep 9.

PubMed [citation]

PMID:: 36096368

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004037737.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: ATP7B c.1142T>G (p.Ile381Ser) results in a non-conservative amino acid change located in the Heavy metal-associated domain, HMA (IPR006121) 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 8e-06 in 249546 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1142T>G has been reported in the literature in individuals affected with Wilson Disease without strong evidence of causality (Coffey_2013, Nagayam_2023), and in one patient the variant was found in cis with another missense variant. These reports 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. The following publications have been ascertained in the context of this evaluation (PMID: 23518715, 36096368). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Sep 29, 2024

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