rs587783644
Variant summary
Our verdict is Likely pathogenic. Variant got 3 ACMG points: 3P and 0B. PP3PM3
This summary comes from the ClinGen Evidence Repository: The NM_004004.6:c.107T>C variant in the GJB2 gene is a missense variant predicted to cause substitution of leucine by proline at amino acid 36 (p.Leu36Pro). The highest population minor allele frequency of the variant is 0.01% (2/19954) in the East Asian population in gnomAD v.2.1.1, which does not meet any population codes based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (BA1/BS1/PM2_Supporting not met). 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 trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2)). The variant has also been reported in five individuals with no pathogenic variant reported in trans (PMIDs:17666888, 26043044, 31581539, 31992338). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_VeryStrong, PP3 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA172208/MONDO:0019497/005
Frequency
Consequence
NM_004004.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJB2 | NM_004004.6 | c.107T>C | p.Leu36Pro | missense_variant | 2/2 | ENST00000382848.5 | |
GJB2 | XM_011535049.3 | c.107T>C | p.Leu36Pro | missense_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJB2 | ENST00000382848.5 | c.107T>C | p.Leu36Pro | missense_variant | 2/2 | 1 | NM_004004.6 | P1 | |
GJB2 | ENST00000382844.2 | c.107T>C | p.Leu36Pro | missense_variant | 1/1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250874Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135644
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461482Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726950
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Hearing impairment Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 20, 2022 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 24, 2017 | - - |
Nonsyndromic genetic hearing loss Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Apr 29, 2019 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at