rs1555937122

Variant names:

• chrX-71223973-T-C
• rs1555937122
• NM_000166.6:c.266T>C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000166.6(GJB1):​c.266T>C​(p.Leu89Pro) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L89V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 8.02
• Publications: 1 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 19 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 27 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-71223972-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 642558.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, 0.993
• PP5: Variant X-71223973-T-C is Pathogenic according to our data. Variant chrX-71223973-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 447428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.266T>C	p.Leu89Pro	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.266T>C	p.Leu89Pro	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.266T>C	p.Leu89Pro	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.266T>C	p.Leu89Pro	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Jan 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have found that this missense change impacts the cellular localization of the GJB1-encoded CX32 protein, preventing the formation of functional CX32 gap junctions (PMID: 27367520). This variant has been reported in multiple individuals affected with CMTX1 (PMID: 26274329, 12457340, 9099841) and it has been reported to segregate with disease in a family affected with X-linked dominant Charcot-Marie-Tooth disease (CMTX1) (PMID: 17714866). This variant is also known as leu238pro in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 89 of the GJB1 protein (p.Leu89Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

not provided Pathogenic:1

Dec 13, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	0.99
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;.;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	.;.;.;.;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;H;H;.;H
PhyloP100		8.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.8	D;.;D;.;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;D;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;.;D
Polyphen		1.0	D;D;D;D;.;D
Vest4		0.98
MutPred		0.95		Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);Loss of stability (P = 0.0153);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		1.0
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: rs1555937122; hg19: chrX-70443823;