rs750294638

Variant summary

Our verdict is Pathogenic. Variant got 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. 13/21 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:4U:1

Conservation

PhyloP100: 10.0

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a topological_domain Extracellular (size 30) in uniprot entity CXA1_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 id is 521097.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP2

Missense variant where missense usually causes diseases, GJA1

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 id is 372744.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr6-121447452-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GJA1	ENST00000282561.4 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	2/2			P1
GJA1	ENST00000649003.1 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	2/2			P1
GJA1	ENST00000650427.1 linkuse as main transcript	c.605G>A	p.Arg202His	missense_variant	2/2			P1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Published functional studies demonstrate a damaging effect (Shibayama et al., 2005); Not observed 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: 14729836, 15637728, 24434540, 16531323, 15879313, 12457340, 18946008, 19338053, 24133447, 16891658, 18831677, 30638447, 33584802, 34630166, 32318302) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Oculodentodigital dysplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Duke University Health System Sequencing Clinic, Duke University Health System

Apr 20, 2023

- -

Oculodentodigital dysplasia, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 30, 2020

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. 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. -

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

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

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

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over