ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.107T>C (p.Leu36Pro)

gnomAD frequency: 0.00004  dbSNP: rs587783644
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV000787988 SCV000927016 uncertain significance Nonsyndromic genetic hearing loss 2019-04-29 reviewed by expert panel curation The allele frequency of the p.Leu36Pro variant in the GJB2 gene is 0.01% (2/19954) of East Asian chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.945, which is above the threshold necessary to apply PP3. This variant has been detected in one patient with hearing loss in trans with 35delG (PM3; PMID:16125251). The variant has also been reported in three individuals with no pathogenic variant found in trans (PMIDs: 17666888, 26043044). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3.
Genetic Services Laboratory, University of Chicago RCV000146004 SCV000193155 pathogenic Hearing impairment 2013-02-08 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000518385 SCV000613503 uncertain significance not specified 2017-04-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001857508 SCV002241983 pathogenic not provided 2022-04-20 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 36 of the GJB2 protein (p.Leu36Pro). This variant is present in population databases (rs587783644, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive nonsyndromic hearing loss (PMID: 16467727, 17666888, 26043044, 29605365, 31581539). 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: 158604). 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. For these reasons, this variant has been classified as Pathogenic.

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