Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
ClinGen
hearing loss
incomplete penetrance
variant classification
variant interpretation
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
09
12
2018
accepted:
24
04
2019
pubmed:
5
6
2019
medline:
28
4
2020
entrez:
5
6
2019
Statut:
ppublish
Résumé
Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants. The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed. The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants. Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
Identifiants
pubmed: 31160754
doi: 10.1038/s41436-019-0535-9
pii: S1098-3600(21)01066-2
pmc: PMC7235630
mid: NIHMS1586971
doi:
Substances chimiques
Connexins
0
GJB2 protein, human
0
Connexin 26
127120-53-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2442-2452Subventions
Organisme : NIDCD NIH HHS
ID : R01 DC011835
Pays : United States
Organisme : NIDCD NIH HHS
ID : R03 DC013866
Pays : United States
Organisme : NIMHD NIH HHS
ID : L60 MD003721
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01 DC015052
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG006834
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR059049
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR069512
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG008666
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01DC011835
Pays : United States
Organisme : NIDCD NIH HHS
ID : R03DC013866
Pays : United States
Organisme : NIDCD NIH HHS
ID : R01DC015052
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Investigateurs
Hela Azaiez
(H)
Kevin T Booth
(KT)
Richard J Smith
(RJ)
Anne B Giersch
(AB)
Cynthia C Morton
(CC)
Xue Z Liu
(XZ)
Mustafa Tekin
(M)
Yu Lu
(Y)
Huijun Yuan
(H)
Hideki Mutai
(H)
Lisa Schimmenti
(L)
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