chrX-71224268-AACCGTCTTC-A

Variant names:

• chrX-71224268-AACCGTCTTC-A
• rs116840823
• NM_000166.6:c.572_580delCCGTCTTCA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP3 PP5

The NM_000166.6(GJB1):​c.572_580delCCGTCTTCA​(p.Thr191_Phe193del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,115 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: GJB1 NM_000166.6 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.32
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000166.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-71224268-AACCGTCTTC-A is Pathogenic according to our data. Variant chrX-71224268-AACCGTCTTC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406229.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.572_580delCCGTCTTCA	p.Thr191_Phe193del	disruptive_inframe_deletion	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.572_580delCCGTCTTCA	p.Thr191_Phe193del	disruptive_inframe_deletion	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.572_580delCCGTCTTCA	p.Thr191_Phe193del	disruptive_inframe_deletion	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.572_580delCCGTCTTCA	p.Thr191_Phe193del	disruptive_inframe_deletion	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095115 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 361899

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54101

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842010

Other (OTH) AF: 0.00 AC: 0 AN: 46073

GnomAD4 genome Cov.: 21

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Pathogenic:1

Nov 26, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 9 nucleotides from exon 2 of the GJB1 mRNA (c.572_580delCCGTCTTCA). This leads to the deletion of 3 amino acid residues in the GJB1 protein (p.Thr191_Phe193del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with Charcot-Marie-Tooth disease (PMID: 9361298, 18379723). This variant is also known as c.573_581delCGTCTTCAT (p.Val192Met194del) in the literature. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant is located in a region of the GJB1 protein where a significant number of previously reported GJB1 missense mutations, deletions, and insertions are found (PMID: 11257785, 19691535, 15574129, 17052905, 9818870, 9361298, 10737979). These observations suggest that alterations within this region may affect protein function, but experiments have not been done to test this possibility. In summary, this variant is a rare deletion that has been observed in affected individuals and overlaps with previously reported Charcot-Marie-Tooth disease variants. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Oct 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB1 c.572_580delCCGTCTTCA (p.Thr191_Phe193del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant was absent in 180670 control chromosomes (gnomAD). c.572_580delCCGTCTTCA has been reported in the literature in individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (Bone_1997, Panosyan_2017, Record_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants involved in the region (Thr191_Phe193), including missense mutations, duplications, deletions, and insertions, were found in patients affected with Charcot-Marie-Tooth disease X-linked dominant 1 in HGMD database, supporting this region is functional important in GJB1 protein. The following publications have been ascertained in the context of this evaluation (PMID: 9361298, 9888385, 28768847, 37284795, 17052905, 18379723). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Jun 17, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs116840823; hg19: chrX-70444118;