ClinVar Miner

Submissions for variant NM_001136473.1(LITAF):c.334G>A (p.Gly112Ser) (rs104894519)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000235719 SCV000255673 pathogenic not provided 2018-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000235719 SCV000293113 pathogenic not provided 2018-12-20 criteria provided, single submitter clinical testing The G112S pathogenic variant has been previously reported in association with CMT1C (Klein et al., 2014; Meggouh et al., 2005; Bennett et al., 2004; Street et al., 2003). Functional studies show that G112S causes mislocalization of the protein to the mitochondria (Lacerda et al., 2014). G112S was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G112S pathogenic variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, we interpret G112S as a pathogenic variant.
GeneReviews RCV000006429 SCV000055877 pathologic Charcot-Marie-Tooth disease, type 1C 2012-10-18 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000006429 SCV000253888 pathogenic Charcot-Marie-Tooth disease, type 1C 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 112 of the LITAF protein (p.Gly112Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with CMT1C in 3 independent multi-generation families, with over 20 affected, variant positive individuals and at least 4 unaffected, variant negative individuals observed (PMID: 15776429, 15122712, 12525712). ClinVar contains an entry for this variant (Variation ID: 6057). Experimental studies have shown that this missense change leads to cellular mislocalization of the LITAF protein and a reduction in the amount of exosomes and secreted exosomal proteins (PMID: 25058650, 23576546). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000006429 SCV000026612 pathogenic Charcot-Marie-Tooth disease, type 1C 2005-04-01 no assertion criteria provided literature only

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