X-71224248-G-C

Variant names:

• chrX-71224248-G-C
• rs879253909
• NM_000166.6:c.541G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000166.6(GJB1):​c.541G>C​(p.Val181Leu) variant causes a missense change involving the alteration of a non-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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.94
• Publications: 8 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, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 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-71224248-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 245705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant X-71224248-G-C is Pathogenic according to our data. Variant chrX-71224248-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 637662.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.541G>C	p.Val181Leu	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.541G>C	p.Val181Leu	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.541G>C	p.Val181Leu	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.541G>C	p.Val181Leu	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Feb 20, 2020

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Located in a critically important domain of the protein.

Charcot-Marie-Tooth disease Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D;D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.0	.;.;.;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.9	L;L;L;L;L
PhyloP100		2.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.5	N;.;N;.;N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D;.;D;.;D
Sift4G	Uncertain	0.038	D;.;D;.;D
Vest4		0.39
ClinPred		0.83	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.99
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: rs879253909; hg19: chrX-70444098;