Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000146015 | SCV000193166 | pathogenic | Hearing impairment | 2013-02-08 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000169347 | SCV000220715 | likely pathogenic | Deafness, autosomal recessive 1A | 2014-09-19 | criteria provided, single submitter | literature only | |
Laboratory for Molecular Medicine, |
RCV000215444 | SCV000271373 | pathogenic | Rare genetic deafness | 2016-03-22 | criteria provided, single submitter | clinical testing | The p.His100Tyr variant in GJB2 has been reported in >15 individuals with hearin g loss including >10 in the compound heterozygous state (Green 1999, Prasad 2000 , Pandya 2003, Feldmann 2004, Snoeckx 2005, Propst 2006, Tang 2006, Pollack 2007 , Putcha 2007, Siem 2010, Gordon 2011, Schimmenti 2011, Lipan 2011, Schimmenti 2 011). It has been identified in 3/66672 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143343083). Addi tional amino acid changes at this location (p.His100Pro, p.His100Leu, and p.His1 00Gln) have been reported in individuals with hearing loss, suggesting that a ch ange at this location may not be tolerated (Gardner 2006, Snoeckx 2005, Bartsch 2010). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein. In summary, this variant meets our criteria to be classified as pathogenic for hearing loss in an autosomal recessive manner. |
ARUP Laboratories, |
RCV000506227 | SCV000603836 | pathogenic | not specified | 2017-03-14 | criteria provided, single submitter | clinical testing | |
Integrated Genetics/Laboratory Corporation of America | RCV000169347 | SCV000919427 | pathogenic | Deafness, autosomal recessive 1A | 2017-09-11 | criteria provided, single submitter | clinical testing | Variant summary: The GJB2 c.298C>T (p.His100Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Connexin, N-terminal domain (IPR013092) (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study showed lack of hemichannel permeability/conductivity associated with this variant (Kim_2016). The variant was found in the control population dataset of ExAC in 5/121260 control chromosomes at a frequency of 0.0000412, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.025). This variant was reported in multiple patients with NSHL (Putcha_2007, Feldmann_2004, Lipan_2011, Burke_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Invitae | RCV000798119 | SCV000937718 | pathogenic | not provided | 2018-11-26 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with tyrosine at codon 100 of the GJB2 protein (p.His100Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs143343083, ExAC 0.02%). This variant has been observed in combination with another GJB2 variant in individuals affected with deafness (PMID: 16467727, 20553101, 11102979, 21287563, 21094084, 21465647, 16222667, 17041943). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 158607). This variant has been reported to affect GJB2 protein function (PMID: 26749107). For these reasons, this variant has been classified as Pathogenic. |
Clinical Molecular Genetics Laboratory, |
RCV000678877 | SCV000805070 | pathogenic | Hearing loss | 2003-02-14 | no assertion criteria provided | clinical testing |