X-71224299-T-G

Position:

• chrX-71224299-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000166.6(GJB1):​c.592T>G​(p.Ser198Ala) 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 (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant X-71224299-T-G is Pathogenic according to our data. Variant chrX-71224299-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 637645.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71224299-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.592T>G	p.Ser198Ala	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.592T>G	p.Ser198Ala	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.592T>G	p.Ser198Ala	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.592T>G	p.Ser198Ala	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital

Oct 29, 2023

The c.592T>G missense substitution predicts an amino acid change from serine to alanine in position 198 in the GJB1 protein, p.(Ser198Ala). It segregates with the disease in the patient’s parents and has been reported in another family with CMT (PMID: 19259128). Another missense variant at the same protein position has been reported as pathogenic (PMID: 9361298). In silico analysis suggests this variant to be damaging (REVEL: 0.8). It is absent in control population (gnomAD).The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PP1_moderate, PM5, PP3_moderate, PM2_supporting, PM3_supporting). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.84	D;D;D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.52	.;.;.;.;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.5	L;L;L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.5	N;.;N;.;N
REVEL	Pathogenic	0.80
Sift	Benign	0.42	T;.;T;.;T
Sift4G	Benign	0.58	T;.;T;.;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.71
MutPred		0.80		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		1.0
MPC		1.7
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.44
gMVP		0.99

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: rs1555937259; hg19: chrX-70444149;