NM_000166.6:c.271G>A

Variant names:

• chrX-71223978-G-A
• rs756928158
• NM_000166.6:c.271G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.271G>A​(p.Val91Met) 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 (★★). ClinVar reports functional evidence for this variant: "SCV001423794: Functional studies in HeLa cells showed decreased expression of the p.Val91Met variant protein in the plasma membrane compared to controls (Tsai et al. 2016). In addition, the variant protein was mainly localized to the cytoplasm and showed fewer gap junction plaques at the intercellular boundaries compared to wild-type. Additional tests were conducted in HEK293T cells where Ca2+ signaling propagation was evaluated. Impaired gap junction permeability was observed and the onset-to-peak duration of the signal was longer in cells expressing the p.Val91Met variant compared to those expressing wild-type protein (Tsai et al. 2016).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V91G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 10.0
• Publications: 16 publications found

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

GJB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001423794: Functional studies in HeLa cells showed decreased expression of the p.Val91Met variant protein in the plasma membrane compared to controls (Tsai et al. 2016). In addition, the variant protein was mainly localized to the cytoplasm and showed fewer gap junction plaques at the intercellular boundaries compared to wild-type. Additional tests were conducted in HEK293T cells where Ca2+ signaling propagation was evaluated. Impaired gap junction permeability was observed and the onset-to-peak duration of the signal was longer in cells expressing the p.Val91Met variant compared to those expressing wild-type protein (Tsai et al. 2016).
• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71223979-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2664352.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-71223978-G-A is Pathogenic according to our data. Variant chrX-71223978-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 195025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.271G>A	p.Val91Met	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.271G>A	p.Val91Met	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.271G>A	p.Val91Met	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.271G>A	p.Val91Met	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.271G>A	p.Val91Met	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.271G>A	p.Val91Met	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00 AC: 0 AN: 165556 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Charcot-Marie-Tooth disease X-linked dominant 1 (2)
2	-	-	not provided (2)
1	-	-	Charcot-Marie-Tooth Neuropathy X (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		10
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.92		Loss of sheet (P = 0.1158)
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.98
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: rs756928158; hg19: chrX-70443828;