The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_004004.5(GJB2):c.101T>C (p.Met34Thr)

CA172206

17000 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
UUID: e8b1ce82-bc97-4baf-b442-294c2a6849cd

HGVS expressions

NM_004004.5:c.101T>C
NM_004004.5(GJB2):c.101T>C (p.Met34Thr)
NC_000013.11:g.20189481A>G
CM000675.2:g.20189481A>G
NC_000013.10:g.20763620A>G
CM000675.1:g.20763620A>G
NC_000013.9:g.19661620A>G
NG_008358.1:g.8495T>C
NM_004004.6:c.101T>C
ENST00000382844.1:c.101T>C
ENST00000382848.4:c.101T>C

Pathogenic

Met criteria codes 4
PS4 PM3_Very Strong PP1 PP3
Not Met criteria codes 19
BP7 BP5 BP2 BP4 BP3 PS1 PS3 PS2 BA1 PP4 PM5 PM1 PM4 PM2 PM6 PVS1 BS4 BS1 BS2

Evidence Links 9

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The filtering allele frequency (the lower threshold of the 95% CI of 510/25108) of the c.101T>C (p.Met34Thr) variant in the GJB2 gene is 1.46% for European (non-Finnish) genomes in gnomAD. This is a high enough frequency that, in the absence of conflicting data, might warrant a benign classification based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). However, based on the evidence outlined below, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs its high allele frequency in population databases. Therefore, the BA1 code will not contribute to the overall classification. The homozygous genotype and compound heterozygous genotype with another variant in GJB2 have shown to be statistically enriched in patients with nonsyndromic sensorineural hearing loss compared to individuals representative of the general population in gnomAD and/or those who underwent carrier screening at Counsyl. (PS4; PMID: 31160754). This study also reported the variant in 27 homozygous affected probands, 17 affected probands with the p.Val37Ile variant in trans, 138 affected probands with a variant asserted to be P/LP in ClinVar, and 78 affected probands with a premature GJB2 termination codon in trans (PM3; PMID 31160754). The REVEL computational prediction analysis tool produced a score of 0.702, which is above the threshold necessary to apply PP3. Most dye transfer and electrical coupling assays support that the variant impacts protein function (PMID: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493); however, some assays showed partial function (PMID: 27884957), and therefore this evidence was not counted. At least 16 segregations of the p.Met34Thr variant in family members have been described (PP1_Strong, PMID: 31160754, 10903123). Of note, the severity of hearing loss is known to be mild on average and there have been multiple accounts of incomplete penetrance of the variant in families/individuals with p.Met34Thr in a biallelic genotype. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic genetic hearing lossbased on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PS4, PP1_Strong, PM3, PP3.
Met criteria codes
PS4
The homozygous genotype and compound het genotype with another path variant in GJB2 has been shown to be statistically enriched in patients with nonsydromic sensorineural hearing loss compared to individuals representative of the general population from carrier screening from Counsyl and/or gnomAD data.

PM3_Very Strong
This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points. PMID 31160754

PP1
This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2

PP3
REVEL score of the variant is 0.702 which is above the HL VCEP's threshold for PP3
Not Met criteria codes
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
Several studies have shown that the p.M34T variant has an impact on the formation and function of the Cx26 channel via dye transfer assays and electrical coupling assays. There were no mouse/ animal models found via lit search. It has also been suggested that this variant may have a dominant negative impact functionally as well though this hasn't really been supported in human cases. PMIDs: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493. This criteria was not counted however because in de Wolf et al. 2016 there was residual function of the p.M34T Cx26 protein, therefore we decided to be conservative and not score this criterion.

PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
This variant was detected in 510/25108 European (Finnish) alleles in gnomAD. The calculated filtering allele frequency in European (non-Finnish) genomes is 0.01462 (1655/128490) with 18 homozygotes. There are 28 homozygotes in gnomAD. However, this variant is statistically enriched in affected populations as shown by Shen et al. 2019 and therefore BA1 should not be applied.

PP4
GJB2 has not been designated by the HL VCEP to be a gene who's variants can be awarded PP4
PM5
The M34T variant is the more established pathogenic variant, therefore, despite the fact that c.101T>G (p.Met34Arg) has been classified as LP by the LMM, that variant would be the one that would be awarded PM5.
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
See BA1

PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
Decreased penetrance is expected of this variant so BS4 wouldn't apply

BS1
see BA1

BS2
There have been at least 2 confirmed accounts of incomplete penetrance of the M34T variant. In two Ashkenazi Jewish compound heterozygotes, the M34T variant was seen in trans with the p.Leu90Pro in one case and the p.Leu56Argfs varint in another case. Both individuals were confirmed to be unaffected by audiological evaluation. However, the homozygous genotype has been shown to be statistically enriched in patients with hearing loss relative to those in the general population. Therefore this code cannot be applied.

Approved on: 2019-06-24
Published on: 2019-06-28
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.