rs370696868

chr13-20189395-C-Achr13-20189395-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1 PM1 PM5 PP3_Strong PP5

The NM_004004.6(GJB2):c.187G>T(p.Val63Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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. V63A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 7.85

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 13 ACMG points.

• PS1: Transcript NM_004004.6 (GJB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2979737
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189395-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94391.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 13-20189395-C-A is Pathogenic according to our data. Variant chr13-20189395-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447443.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB2	NM_004004.6	c.187G>T	p.Val63Leu	missense_variant	2/2	ENST00000382848.5
GJB2	XM_011535049.3	c.187G>T	p.Val63Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB2	ENST00000382848.5	c.187G>T	p.Val63Leu	missense_variant	2/2	1	NM_004004.6	P1
GJB2	ENST00000382844.2	c.187G>T	p.Val63Leu	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251252 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461062 Hom.: 0 Cov.: 33 AF XY: 0.0000206 AC XY: 15 AN XY: 726662

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000445 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 10, 2023	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 63 of the GJB2 protein (p.Val63Leu). This variant is present in population databases (rs370696868, gnomAD 0.02%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 12792423, 25266519, 34403091; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447443). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Val63 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 19, 2023	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant is statistically significantly enriched in affected patients as compared to ethnically matched controls. Computational tools predict that this variant is damaging. -

Autosomal recessive nonsyndromic hearing loss 1A Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal dominant nonsyndromic hearing loss 3A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 08, 2023

The inherited heterozygous c.187G>T p.(Val63Leu) variant identified in the GJB2 gene has previously been reported as heterozygous in multiple individuals with non‐syndromic hearing loss [PMID: 21557232, 26252218, 26043044, 19366456, 24612839, 25266519, others] and as compound heterozygous in at least two families with recessively inherited hearing loss [PMID: 19707039, 24507663]. This variant has been deposited in ClinVar [ClinVar ID:447443] as Variant of Uncertain Significance (2 submissions) and Likely Pathogenic (1 submission), and was classified as a Variant of Uncertain by a recent study[PMID: 36048236]. In population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), the c.187G>T variant is observed at ~0.0027% minor allele frequency across populations (with 0 homozygotes), including ~0.03% minor allele frequency in East Asian sub-population which is higher than the expected maximum allele frequency for a pathogenic variant in the GJB2-related dominant hearing loss [https://cspec.genome.network/cspec/ui/svi/doc/GN005]. The c.187G>T variant in GJB2is located in exon 2 of this 2-exon gene and is predicted to replace an evolutionarily conserved valine amino acid with leucine at position 63 of the encoded protein.In silico predictions are in favor of damaging effect for p.(Val63Leu) [REVEL = 0.929]; however, there are no functional studies to support or refute these predictions. Due to the lack of compelling evidence for its pathogenicity, this inherited heterozygous c.187G>T p.(Val63Leu) variant identified in GJB2 is classified as a Variant of Uncertain Significance for GJB2-related autosomal dominant hearing loss. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.0	D;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.025	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.93		Gain of catalytic residue at V63 (P = 0.0426);Gain of catalytic residue at V63 (P = 0.0426);Gain of catalytic residue at V63 (P = 0.0426);
MVP		0.97
MPC		0.28
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.95

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: rs370696868; hg19: chr13-20763534;