NM_000165.5(GJA1):c.389T>C (p.Ile130Thr) AND Oculodentodigital dysplasia, autosomal recessive

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 10, 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:: RCV000549390.5

Allele description [Variation Report for NM_000165.5(GJA1):c.389T>C (p.Ile130Thr)]

NM_000165.5(GJA1):c.389T>C (p.Ile130Thr)

Gene:

GJA1:gap junction protein alpha 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q22.31

Genomic location:

Preferred name:

NM_000165.5(GJA1):c.389T>C (p.Ile130Thr)

HGVS:

NC_000006.12:g.121447236T>C
NG_008308.1:g.16638T>C
NM_000165.5:c.389T>CMANE SELECT
NP_000156.1:p.Ile130Thr
LRG_1289t1:c.389T>C
LRG_1289:g.16638T>C
LRG_1289p1:p.Ile130Thr
NC_000006.11:g.121768382T>C
NM_000165.4:c.389T>C

Protein change:

I130T

Links:

dbSNP: rs1554201017

NCBI 1000 Genomes Browser:

rs1554201017

Molecular consequence:

NM_000165.5:c.389T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Oculodentodigital dysplasia, autosomal recessive
Synonyms:: OCULODENTOOSSEOUS DYSPLASIA, AUTOSOMAL RECESSIVE; ODDD, AUTOSOMAL RECESSIVE; ODOD, AUTOSOMAL RECESSIVE
Identifiers:: MONDO: MONDO:0009768; MedGen: C2749477; Orphanet: 2710; OMIM: 257850

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000647918	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 10, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12457340, 18660473, 22826718, 15879313, 18077386, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000647918

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 10, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia.

Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW.

Am J Hum Genet. 2003 Feb;72(2):408-18. Epub 2002 Nov 27.

PubMed [citation]

PMID:: 12457340
PMCID:: PMC379233

Expanding the neurologic phenotype of oculodentodigital dysplasia in a 4-generation Hispanic family.

Amador C, Mathews AM, Del Carmen Montoya M, Laughridge ME, Everman DB, Holden KR.

J Child Neurol. 2008 Aug;23(8):901-5. doi: 10.1177/0883073808317730.

PubMed [citation]

PMID:: 18660473

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000647918.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 130 of the GJA1 protein (p.Ile130Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with oculodentodigital dysplasia (PMID: 12457340, 18660473, 22826718). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 470215). 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 GJA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GJA1 function (PMID: 15879313, 18077386). For these reasons, this variant has been classified as 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: Feb 20, 2024

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