NM_004004.6(GJB2):c.110T>C (p.Val37Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 20, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000520583.7

Allele description [Variation Report for NM_004004.6(GJB2):c.110T>C (p.Val37Ala)]

NM_004004.6(GJB2):c.110T>C (p.Val37Ala)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.110T>C (p.Val37Ala)

HGVS:

NC_000013.11:g.20189472A>G
NG_008358.1:g.8504T>C
NM_004004.6:c.110T>CMANE SELECT
NP_003995.2:p.Val37Ala
LRG_1350t1:c.110T>C
LRG_1350:g.8504T>C
LRG_1350p1:p.Val37Ala
NC_000013.10:g.20763611A>G
NM_004004.5:c.110T>C
NM_004004.6(GJB2):c.110T>CMANE SELECT
p.Val37Ala

Protein change:

V37A

Links:

dbSNP: rs141774369

NCBI 1000 Genomes Browser:

rs141774369

Molecular consequence:

NM_004004.6:c.110T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000617689	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 10, 2023)	germline	clinical testing	Citation Link,
SCV004309301	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15365987, 17666888, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000617689

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 10, 2023)

germline

clinical testing

Citation Link,

SCV004309301

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

GJB2: the spectrum of deafness-causing allele variants and their phenotype.

Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo I, Van Camp G, Smith RJ.

Hum Mutat. 2004 Oct;24(4):305-11.

PubMed [citation]

PMID:: 15365987
PMCID:: PMC10519371

A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000617689.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed heterozygous with no other GJB2 variants in patients with hearing loss in published literature (Azaiez et al., 2004; Putcha et al., 2007; Lipan et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 21287563, 25087612, 27466889, 15365987, 17666888)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004309301.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the GJB2 protein (p.Val37Ala). This variant is present in population databases (rs141774369, gnomAD 0.04%). This missense change has been observed in individual(s) with autosomal recessive deafness (PMID: 15365987, 17666888). ClinVar contains an entry for this variant (Variation ID: 449490). 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.Val37 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15365987, 17666888). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 20, 2024

ClinVar

Relating variation to medicine