Submissions for variant NM_001005360.2(DNM2):c.1106G>A (p.Arg369Gln) (rs121909089)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000145900	SCV000193037	pathogenic	Myopathy, centronuclear	2013-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV000701394	SCV000830194	pathogenic	Charcot-Marie-Tooth disease, dominant intermediate B	2019-04-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 369 of the DNM2 protein (p.Arg369Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with centronuclear myopathy in several families (PMID: 16227997, 25501959, 26908122) and has been reported in individuals affected with centronuclear myopathy with and without myotonia (PMID: 19130742, 24366529). ClinVar contains an entry for this variant (Variation ID: 7279). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Variants that disrupt the p.Arg369 amino acid residue in DNM2 have been observed in affected individuals (PMID: 16227997, 22613877, 25492887, 20817456, 24016602, 20529869, 28676641). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000007702	SCV000027903	pathogenic	Myopathy, centronuclear, 1	2005-11-01	no assertion criteria provided	literature only

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