rs1554200992

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000165.5(GJA1):c.119C>T(p.Ala40Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A40A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GJA1
NM_000165.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.91

Publications

2 publications found

Variant links:

Genes affected

GJA1 (HGNC:4274): (gap junction protein alpha 1) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]

GJA1 Gene-Disease associations (from GenCC):

hypoplastic left heart syndrome 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
oculodentodigital dysplasia
Inheritance: AD, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant palmoplantar keratoderma and congenital alopecia
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P
erythrokeratodermia variabilis et progressiva 3
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
oculodentodigital dysplasia, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
craniometaphyseal dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 3
Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Hallermann-Streiff syndrome
Inheritance: AR Classification: LIMITED Submitted by: G2P
craniometaphyseal dysplasia, autosomal recessive
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

GJA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000165.5

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GJA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2784 (below the threshold of 3.09). Trascript score misZ: 3.3775 (above the threshold of 3.09). GenCC associations: The gene is linked to craniometaphyseal dysplasia, autosomal recessive, erythrokeratodermia variabilis et progressiva 3, oculodentodigital dysplasia, autosomal dominant palmoplantar keratoderma and congenital alopecia, hypoplastic left heart syndrome 1, craniometaphyseal dysplasia, syndactyly type 3, oculodentodigital dysplasia, autosomal recessive, nonsyndromic genetic hearing loss, Hallermann-Streiff syndrome, erythrokeratodermia variabilis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 6-121446966-C-T is Pathogenic according to our data. Variant chr6-121446966-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 435323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5 link	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 2	ENST00000282561.4	NP_000156.1	P17302A0A654IBU3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJA1	ENST00000282561.4 link	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3	P17302
GJA1	ENST00000647564.1 link	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 2			ENSP00000497565.1	P17302
GJA1	ENST00000649003.1 link	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 2			ENSP00000497283.1	P17302
GJA1	ENST00000650427.1 link	c.119C>T	p.Ala40Val	missense_variant	Exon 2 of 2			ENSP00000497367.1	P17302

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727152

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111822

Other (OTH)

AF:

0.00

AC:

AN:

60390

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Oculodentodigital dysplasia

Pathogenic:1

Jan 28, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

May 16, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect showing compromised channel function and a complete lack of functional electrical coupling (Shibayama et al., 2005); Not observed at 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: 16418219, 16378922, 34094714, 12457340, 32224865, 25327171, 30628995, 15879313) -

Oculodentodigital dysplasia, autosomal recessive

Pathogenic:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the GJA1 protein (p.Ala40Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant oculodentodigital dysplasia (PMID: 12457340, 25327171, 30628995). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 435323). 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). For these reasons, this variant has been classified as Pathogenic. -

Atrioventricular septal defect and common atrioventricular junction;C0812437:Oculodentodigital dysplasia;C1861366:Syndactyly type 3;C2749477:Oculodentodigital dysplasia, autosomal recessive;C2931244:Craniometaphyseal dysplasia, autosomal recessive;C4304669:Autosomal dominant palmoplantar keratoderma and congenital alopecia;C4479619:Erythrokeratodermia variabilis et progressiva 3;C4551854:Hypoplastic left heart syndrome 1

Pathogenic:1

Jul 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

.;.;.;.;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.6

L;L;L;L;L

PhyloP100

7.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.6

.;.;D;.;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.017

.;.;D;.;.

Sift4G

Uncertain

0.0020

.;.;D;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.96

MutPred

0.95

Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);

MVP

0.97

MPC

1.4

ClinPred

0.98

GERP RS

6.2

Varity_R

0.66

gMVP

0.96

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over