NM_000165.5:c.605G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_000165.5(GJA1):c.605G>A(p.Arg202His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GJA1
NM_000165.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 10.0

Publications

22 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 12 ACMG points.

PM1

In a hotspot region, there are 4 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-121447451-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521097.

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, 0.988

PP5

Variant 6-121447452-G-A is Pathogenic according to our data. Variant chr6-121447452-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372744.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5 link	c.605G>A	p.Arg202His	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.605G>A	p.Arg202His	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3	P17302
GJA1	ENST00000647564.1 link	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497565.1	P17302
GJA1	ENST00000649003.1 link	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497283.1	P17302
GJA1	ENST00000650427.1 link	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497367.1	P17302

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 24, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect (PMID: 15879313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14729836, 15637728, 24434540, 16531323, 12457340, 18946008, 19338053, 24133447, 16891658, 18831677, 30638447, 33584802, 34630166, 32318302, 15879313) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oculodentodigital dysplasia

Pathogenic:1

Apr 20, 2023

Duke University Health System Sequencing Clinic, Duke University Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oculodentodigital dysplasia, autosomal recessive

Uncertain:1

Jun 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Experimental studies have shown that this missense change leads to intracellular retention, reduced gap junction plaque formation and impaired coupling (PMID:¬†15879313, 16531323). This variant has been reported in several individuals affected with¬†oculodentodigital dysplasia¬†(PMID: 12457340, 18946008). ClinVar contains an entry for this variant (Variation ID: 372744). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with histidine at codon 202 of the GJA1 protein (p.Arg202His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

.;.;.;.;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;M

PhyloP100

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-4.7

.;.;D;.;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.98

MutPred

0.91

Gain of ubiquitination at K206 (P = 0.0804);Gain of ubiquitination at K206 (P = 0.0804);Gain of ubiquitination at K206 (P = 0.0804);Gain of ubiquitination at K206 (P = 0.0804);Gain of ubiquitination at K206 (P = 0.0804);

MVP

0.99

MPC

0.88

ClinPred

1.0

GERP RS

5.8

Varity_R

0.74

gMVP

0.97

Mutation Taster

=56/44

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