6-121447260-G-A

Variant names:

• chr6-121447260-G-A
• rs1554201019
• NM_000165.5:c.413G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000165.5(GJA1):​c.413G>A​(p.Gly138Asp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G138S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr6-121447259-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 537756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.939
• PP5: Variant 6-121447260-G-A is Pathogenic according to our data. Variant chr6-121447260-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 470216.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	c.413G>A	p.Gly138Asp	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.413G>A	p.Gly138Asp	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3
GJA1	ENST00000647564.1	c.413G>A	p.Gly138Asp	missense_variant	Exon 2 of 2			ENSP00000497565.1
GJA1	ENST00000649003.1	c.413G>A	p.Gly138Asp	missense_variant	Exon 2 of 2			ENSP00000497283.1
GJA1	ENST00000650427.1	c.413G>A	p.Gly138Asp	missense_variant	Exon 2 of 2			ENSP00000497367.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Oculodentodigital dysplasia Pathogenic:2

Mar 07, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Oculodentodigital dysplasia, autosomal recessive Pathogenic:1

Jan 30, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located at the L2 domain of the GJA1 protein that has been shown to be required for its binding to calmodulin and is enriched for missense variants in individuals affected with ODDD (PMID: 17901047, 19338053). Two additional missense substitutions at this codon (p.Gly138Arg, p.Gly138Ser) have been determined to be pathogenic (PMID: 18003637, 12457340, 27226478, 18946008, 25388818). This suggests that the glycine residue is critical for GJA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that is absent from the population and reported in affected individuals. It is located in a functional domain of GJ1A and affects a residue important for protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in an individual affected with oculodentodigital dysplasia (PMID: 18946008). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 138 of the GJA1 protein (p.Gly138Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D;D;D;D;D
Eigen	Benign	0.062
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;.;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.77	.;.;N;.;.
REVEL	Pathogenic	0.68
Sift	Benign	0.18	.;.;T;.;.
Sift4G	Benign	0.24	.;.;T;.;.
Polyphen		0.78	P;P;P;P;P
Vest4		0.92
MutPred		0.80		Loss of MoRF binding (P = 0.0707);Loss of MoRF binding (P = 0.0707);Loss of MoRF binding (P = 0.0707);Loss of MoRF binding (P = 0.0707);Loss of MoRF binding (P = 0.0707);
MVP		0.99
MPC		1.1
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.46
gMVP		0.97
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554201019; hg19: chr6-121768406;