rs111033335

Positions:

• chr13-20188981-TTCCAGACAC-TGAATGTCATGAACACTG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004004.6(GJB2):​c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC​(p.Val198fs) variant causes a frameshift, stop gained, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJB2 NM_004004.6 frameshift, stop_gained, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.94

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. 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 are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-20188982-TCCAGACAC-GAATGTCATGAACACTG is Pathogenic according to our data. Variant chr13-20188982-TCCAGACAC-GAATGTCATGAACACTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB2	NM_004004.6	c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC	p.Val198fs	frameshift_variant, stop_gained, missense_variant	2/2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC	p.Val198fs	frameshift_variant, stop_gained, missense_variant	2/2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC	p.Val198fs	frameshift_variant, stop_gained, missense_variant	2/2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.592_600delGTGTCTGGAinsCAGTGTTCATGACATTC	p.Val198fs	frameshift_variant, stop_gained, missense_variant	1/1	6		ENSP00000372295.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2024	Identified in an additional patient with hearing loss in published literature, however, it was unclear if a second variant was identified (PMID: 17041943); Frameshift variant predicted to result in abnormal protein length as the last 29 amino acid(s) are replaced with 3 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20154630, 17041943) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2019	- -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2022	Variant summary: GJB2 c.592_600delins17 (p.Val198GlnfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 246636 control chromosomes (gnomAD and publication data). c.592_600delins17 has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (example: Tang _2006, and Chan_2010). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Mar 31, 2010

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 27, 2015

The p.Val198fs variant in GJB2 has been reported in 3 individuals with hearing l oss (Tang 2006, Chan 2010, LMM unpublished data), 2 of whom were compound hetero zygous with a second pathogenic or likely pathogenic GJB2 variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 198 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic for hearing loss in an autosomal recessive manner (http://www.partners. org/personalizedmedicine/LMM) based on the predicted impact of the variant and m ultiple occurrences with pathogenic GJB2 variants in individuals with hearing lo ss. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033335; hg19: chr13-20763121;