NM_000052.7(ATP7A):c.3137C>T (p.Thr1046Ile) AND Menkes kinky-hair syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 4, 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:: RCV001265560.2

Allele description [Variation Report for NM_000052.7(ATP7A):c.3137C>T (p.Thr1046Ile)]

NM_000052.7(ATP7A):c.3137C>T (p.Thr1046Ile)

Gene:

ATP7A:ATPase copper transporting alpha [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq21.1

Genomic location:

Preferred name:

NM_000052.7(ATP7A):c.3137C>T (p.Thr1046Ile)

HGVS:

NC_000023.11:g.78031425C>T
NG_013224.2:g.125729C>T
NM_000052.7:c.3137C>TMANE SELECT
NM_001282224.2:c.2903C>T
NP_000043.4:p.Thr1046Ile
NP_001269153.1:p.Thr968Ile
NC_000023.10:g.77286923C>T
NM_000052.4:c.3137C>T
NM_000052.6:c.3137C>T
NR_104109.2:n.310C>T

Protein change:

T1046I

Links:

dbSNP: rs1064796648

NCBI 1000 Genomes Browser:

rs1064796648

Molecular consequence:

NM_000052.7:c.3137C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282224.2:c.2903C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104109.2:n.310C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Menkes kinky-hair syndrome (MNK)
Synonyms:: Kinky hair disease; Copper transport disease; Menkes Disease
Identifiers:: MONDO: MONDO:0010651; MedGen: C0022716; Orphanet: 565; OMIM: 309400

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Rattus norvegicus phosphate cytidylyltransferase 1, choline, beta (Pcyt1b), mRNA
Rattus norvegicus phosphate cytidylyltransferase 1, choline, beta (Pcyt1b), mRNA
gi|27465630|ref|NM_173151.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001443715	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572472	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30809870, 25150085, 33999244 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001443715

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 10, 2019)

germline

clinical testing

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

SCV002572472

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Aug 4, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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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

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

ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis.

Fujisawa C, Kodama H, Hiroki T, Akasaka Y, Hamanoue M.

Pediatr Int. 2019 Apr;61(4):345-350. doi: 10.1111/ped.13817. Epub 2019 Apr 16.

PubMed [citation]

PMID:: 30809870

See all PubMed Citations (4)

Details of each submission

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001443715.1

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

Description

The p.Thr1046Ile variant has been reported in two affected patients (PMID: 25150085, 30809870). The variant also has an entry by a clinical laboratory in the ClinVar database as likely pathogenic (Variation ID: 423830). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. In silico analyses support a deleterious effect of the c.3137C>T (p.Thr1046Ile) variant on protein function. This result was confirmed by Sanger sequencing. Analysis of the parental samples showed the mother is positive for this variant. Based on the available evidence, the c.3137C>T (p.Thr1046Ile) variant is classified as Likely Pathogenic.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572472.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ATP7A c.3137C>T (p.Thr1046Ile) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183387 control chromosomes. c.3137C>T has been reported in the literature in individuals affected with Menkes Kinky-Hair Syndrome (Gu_2014, Fijisawa_2019, Shur_2021). These data indicate that the variant may be associated with disease. Other variants located nearby have been reported in association with Menkes Syndrome in HGMD (eg. p.D1044G, p.T1048I, etc). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Dec 11, 2022

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