X-71224248-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000166.6(GJB1):​c.541G>T​(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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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 Likely_pathogenic. Variant got 6 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, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.541G>T	p.Val181Leu	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.541G>T	p.Val181Leu	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	XM_011530907.3	c.541G>T	p.Val181Leu	missense_variant	Exon 2 of 2		XP_011529209.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1093879 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360927

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Oct 08, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in an individual affected with Charcot-Marie-Tooth disease type X (PMID: 18380031). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 181 of the GJB1 protein (p.Val181Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This missense change is located in a region of the GJB1 protein where a significant number of previously reported GJB1 missense mutations are found (PMID: 9361298, 20128140, 17100997, 16922730,15006706,9187667). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. A different missense substitution at this codon (p.Val181Ala) has been determined to be pathogenic (PMID: 14627639). In addition, a different missense substitution at this codon (p.Val181Met) has been reported in a patient with Charcot-Marie-Tooth disease type X (PMID: 9361298). This suggests that the valine residue is critical for GJB1 protein function and that other missense substitutions at this position may also be pathogenic. -

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	0.87	D
LIST_S2	Uncertain	0.89	.;.;.;.;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
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
Polyphen		0.95	P;P;P;P;P
Vest4		0.39
MutPred		0.60		Loss of glycosylation at S182 (P = 0.0934);Loss of glycosylation at S182 (P = 0.0934);Loss of glycosylation at S182 (P = 0.0934);Loss of glycosylation at S182 (P = 0.0934);Loss of glycosylation at S182 (P = 0.0934);
MVP		1.0
MPC		1.2
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.76
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: rs879253909; hg19: chrX-70444098;