rs750294638

Variant names:

• chr6-121447452-G-A
• rs750294638
• NM_000165.5:c.605G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• 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, Hallermann-Streiff syndrome, syndactyly type 3, oculodentodigital dysplasia, nonsyndromic genetic hearing loss, hypoplastic left heart syndrome 1, autosomal dominant palmoplantar keratoderma and congenital alopecia, oculodentodigital dysplasia, autosomal recessive, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, 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 id is 372744.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr6-121447452-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497565.1
GJA1	ENST00000649003.1	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497283.1
GJA1	ENST00000650427.1	c.605G>A	p.Arg202His	missense_variant	Exon 2 of 2			ENSP00000497367.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	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) -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2020

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	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
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	D
LIST_S2	Pathogenic	0.99	.;.;.;.;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M
PrimateAI	Pathogenic	0.86	D
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	D
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

Other links and lift over

dbSNP: rs750294638; hg19: chr6-121768598; COSMIC: COSV56997002;