Submissions for variant NM_000166.6(GJB1):c.614A>G (p.Asn205Ser) (rs104894822)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000537008	SCV000658918	pathogenic	Charcot-Marie-Tooth Neuropathy X	2019-03-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 205 of the GJB1 protein (p.Asn205Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with X-linked Charcot-Marie-Tooth disease (CMTX) in 2 families (PMID: 24327141, 10071100), and has also been reported in multiple unrelated individuals affected with CMTX (PMID: 9452099, 9401007, 12497641, 19259128, 27544631, 28469099). ClinVar contains an entry for this variant (Variation ID: 10442). While one experimental study did not detect a functional effect for this variant (PMID: 15006706), a second study found that it caused increased perinuclear localization compared to wildtype GJB1 protein (PMID: 12111842). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000991856	SCV001143682	pathogenic	not provided	2019-08-15	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/201577 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. The gain of a new splice site is predicted. Results on protein functions were conflicting. Moderate co-segregation with disease in affected individuals from a single family.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000991856	SCV001245767	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000011187	SCV000031414	pathogenic	X-linked hereditary motor and sensory neuropathy	1999-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000011187	SCV000040509	pathologic	X-linked hereditary motor and sensory neuropathy	2010-04-15	no assertion criteria provided	curation	Converted during submission to Pathogenic.

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