NM_000165.5:c.32T>C

Variant names:

• chr6-121446879-T-C
• rs121912969
• NM_000165.5:c.32T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000165.5(GJA1):​c.32T>C​(p.Leu11Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L11F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 10 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 12 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 chr6-121446878-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29668.Status of the report is no_assertion_criteria_provided, 0 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, 0.994
• PP5: Variant 6-121446879-T-C is Pathogenic according to our data. Variant chr6-121446879-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 16993.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000165.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	NM_000165.5	MANE Select	c.32T>C	p.Leu11Pro	missense	Exon 2 of 2	NP_000156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	ENST00000282561.4	TSL:1 MANE Select	c.32T>C	p.Leu11Pro	missense	Exon 2 of 2	ENSP00000282561.3
	GJA1	ENST00000647564.1		c.32T>C	p.Leu11Pro	missense	Exon 2 of 2	ENSP00000497565.1
	GJA1	ENST00000649003.1		c.32T>C	p.Leu11Pro	missense	Exon 2 of 2	ENSP00000497283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000725 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oculodentodigital dysplasia Pathogenic:1

May 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.98		Gain of disorder (P = 0.014)
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		1.0
Mutation Taster		=0/100	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: rs121912969; hg19: chr6-121768025;