rs794729675

Positions:

• chr6-121446978-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP2 PP5_Very_Strong

The NM_000165.5(GJA1):​c.131C>T​(p.Ala44Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 6.17

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 5 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 gene, where missense usually causes diseases (based on misZ statistic), GJA1. . Gene score misZ 1.2784 (greater than the threshold 3.09). Trascript score misZ 3.3775 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP5: Variant 6-121446978-C-T is Pathogenic according to our data. Variant chr6-121446978-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 203469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5	c.131C>T	p.Ala44Val	missense_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA1	ENST00000282561.4	c.131C>T	p.Ala44Val	missense_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1	c.131C>T	p.Ala44Val	missense_variant	2/2			P1
GJA1	ENST00000649003.1	c.131C>T	p.Ala44Val	missense_variant	2/2			P1
GJA1	ENST00000650427.1	c.131C>T	p.Ala44Val	missense_variant	2/2			P1

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

Erythrokeratodermia variabilis et progressiva 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 17, 2019	- -

Oculodentodigital dysplasia, autosomal recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 07, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 44 of the GJA1 protein (p.Ala44Val). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJA1 function (PMID: 25398053, 30631135). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 203469). This missense change has been observed in individual(s) with erythrokeratodermia variabilis et progressiva (PMID: 25398053, 30628963; Invitae). In at least one individual the variant was observed to be de novo. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Uncertain	0.57	D;D;D;D;D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.86	.;.;.;.;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.46	T;T;T;T;T
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	-2.3	N;N;N;N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.5	.;.;N;.;.
REVEL	Pathogenic	0.82
Sift	Benign	1.0	.;.;T;.;.
Sift4G	Benign	1.0	.;.;T;.;.
Polyphen		0.17	B;B;B;B;B
Vest4		0.41
MutPred		0.50		Loss of catalytic residue at A44 (P = 0.02);Loss of catalytic residue at A44 (P = 0.02);Loss of catalytic residue at A44 (P = 0.02);Loss of catalytic residue at A44 (P = 0.02);Loss of catalytic residue at A44 (P = 0.02);
MVP		0.93
MPC		0.75
ClinPred		0.34	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.88

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: rs794729675; hg19: chr6-121768124;