X-71224248-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1 PM1 PM2 PM5 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V181E) has been classified as Likely pathogenic.

• 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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000166.6 (GJB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 637662
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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-71224249-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 234844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.541G>T	p.Val181Leu	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.541G>T	p.Val181Leu	missense_variant	2/2
GJB1	XM_011530907.3	c.541G>T	p.Val181Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.541G>T	p.Val181Leu	missense_variant	2/2	1	NM_000166.6	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2016

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. 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. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Charcot-Marie-Tooth disease type X (PMID: 18380031). 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. 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. 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"). -

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
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
MutationTaster	Benign	1.0	D;D;D
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;