Submissions for variant NM_004004.6(GJB2):c.298C>T (p.His100Tyr) (rs143343083)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	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,Partners HealthCare Personalized 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, Molecular Genetics and Genomics, 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,Johns Hopkins All Children's Hospital	RCV000678877	SCV000805070	pathogenic	Hearing loss	2003-02-14	no assertion criteria provided	clinical testing