Submissions for variant NM_000166.6(GJB1):c.164C>T (p.Thr55Ile) (rs104894824)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486043	SCV000568357	pathogenic	not provided	2017-02-21	criteria provided, single submitter	clinical testing	The T55I variant in the GJB1 gene has been previously reported several times in association with CMTX1 (Karadimas et al., 1999; Panas et al., 2001; Hahn et al., 2001). Functional studies indicate that T55I impairs protein trafficking to the cell membrane and inhibits the formation of functional gap junctions (Abrams et al., 2017; Kleopa et al., 2002). The T55I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T55I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, multiple missense variants in nearby residues and at the same residue (T55A/R) have been reported in the Human Gene Mutation Database in association with GJB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.
OMIM	RCV000011191	SCV000031418	pathogenic	X-linked hereditary motor and sensory neuropathy	2001-11-27	no assertion criteria provided	literature only
GeneReviews	RCV000011191	SCV000040499	pathologic	X-linked hereditary motor and sensory neuropathy	2010-04-15	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Inherited Neuropathy Consortium	RCV000789872	SCV000929257	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only