Submissions for variant NM_004004.6(GJB2):c.239A>C (p.Gln80Pro)

gnomAD frequency: 0.00001  dbSNP: rs727504302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154345	SCV000204008	likely pathogenic	Rare genetic deafness	2014-01-03	criteria provided, single submitter	clinical testing	The Gln80Pro variant in GJB2 has been reported in at least 2 individuals with he aring loss, one of whom is reported to also carry the pathogenic GJB6 deletion i n trans with this variant (Ferraris 2002, Snoeckx 2005, Rodriguez-Paris 2011). I t has also been identified in an individual with hearing loss by our laboratory , who carried a pathogenic GJB2 variant in trans with this variant. In addition , the Gln80Pro variant has not been identified in large population studies and c omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) suggest that the Gln80Pro variant may impact the protein . In summary, this variant is likely pathogenic, though additional functional st udies are required to fully establish its clinical significance.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000505508	SCV000599738	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000505508	SCV000793831	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2018-04-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001288584	SCV001475810	likely pathogenic	not provided	2020-03-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Statistically enriched in uncharacterized patients vs. unmatched population data. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288584	SCV001580693	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 80 of the GJB2 protein (p.Gln80Pro). This variant is present in population databases (rs727504302, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive deafness (PMID: 16532460, 30094485). ClinVar contains an entry for this variant (Variation ID: 177735). 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. This variant disrupts the p.Gln80 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15855033, 30473554). 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.
GeneDx	RCV001288584	SCV003927452	likely pathogenic	not provided	2023-05-11	criteria provided, single submitter	clinical testing	Observed in unrelated patients with hearing loss in published literature, but additional information about genotype and phenotype is not available (Snoeckx et al., 2005; Putcha et al., 2007); 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: 30094485, 12325027, 25388846, 17666888, 21738759, 16532460, 31160754, 16380907)