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

gnomAD frequency: 0.00003  dbSNP: rs143343083

Total submissions: 13

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	Autosomal recessive nonsyndromic hearing loss 1A	2014-09-19	criteria provided, single submitter	literature only
Laboratory for Molecular Medicine,Mass General Brigham 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	RCV000798119	SCV000603836	pathogenic	not provided	2020-10-07	criteria provided, single submitter	clinical testing	The GJB2 c.298C>T; p.His100Tyr variant (rs143343083) has been reported multiple times in the literature in individuals with hearing loss who were compound heterozygous with another pathogenic GJB2 variant (Dodson 2011, Green 1999, Putcha 2007, Siemering 2006, Snoeckx 2005). Additionally, functional studies suggest the variant protein is unable to function properly as a homotypic gap junction (Kim 2016). This variant has also been reported to the ClinVar database (Variation ID: 158607). It is found in the general population with an overall allele frequency of 0.001% (3/250900 alleles) in the Genome Aggregation Database. The histidine at codon 100 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Dodson KM et al. Vestibular dysfunction in DFNB1 deafness. Am J Med Genet A. 2011 May;155A(5):993-1000. Green GE et al. Carrier rates in the midwestern United States for GJB2 mutations causing inherited deafness. JAMA. 1999 Jun 16;281(23):2211-6. Kim HR et al. The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis. Hum Genet. 2016 Mar;135(3):287-98. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Siemering K et al. Detection of mutations in genes associated with hearing loss using a microarray-based approach. J Mol Diagn. 2006 Sep;8(4):483-9. Snoeckx RL et al. GJB2 mutations and degree of hearing loss: a multicenter study. Am J Hum Genet. 2005 Dec;77(6):945-57.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169347	SCV000919427	pathogenic	Autosomal recessive nonsyndromic hearing loss 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	2021-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000798119	SCV001371290	pathogenic	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000798119	SCV001762221	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000798119	SCV001825360	pathogenic	not provided	2021-12-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on hemichannel permeability (Kim et al., 2016); Different missense changes at this residue (p.(H100L), p.(H100P), p.(H100Q)) have been reported as pathogenic in the published literature in association with autosomal recessive nonsyndromic hearing loss (Snoeckx et al., 2005; Bartsch et al., 2010; Kim et al., 2016); 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: 25087612, 10376574, 31160754, 25388846, 20553101, 14694360, 17935238, 21287563, 12865758, 11102979, 17666888, 16950989, 17041943, 16380907, 21465647, 31980526, 16931589, 26778469, 16467727, 26749107, 20234132)
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital	RCV000678877	SCV000805070	pathogenic	Hearing loss	2003-02-14	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals	RCV001374647	SCV001571569	pathogenic	nonsyndromic sensorineural hearing loss	2020-08-15	no assertion criteria provided	clinical testing
PerkinElmer Genomics	RCV000798119	SCV002024269	pathogenic	not provided	2019-02-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169347	SCV002086052	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-07-07	no assertion criteria provided	clinical testing