ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.368A>G (p.His123Arg) (rs397515442)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254797 SCV000321716 pathogenic not provided 2016-08-18 criteria provided, single submitter clinical testing The H123R pathogenic variant in the GDAP1 gene has been reported previously in multiple unrelatedfamilies with autosomal dominant Charcot-Marie-Tooth (CMT) disease (Zimon et al., 2011; Auranenet al., 2013; Pezzini et al., 2016) . The H123R variant has been determined to be a founder mutationin the Finnish population and accounts for up to 14% of Finnish individuals with a clinical diagnosis ofCMT2 (Auranen et al., 2013). The H123R variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This conservative amino acidsubstitution occurs at a position that is conserved in mammals and in silico analysis is inconsistent inits predictions as to whether or not the variant is damaging to the protein structure/function. Missensevariants in nearby residues (R120G, R120W, R120Q, Q122K, D129H) have been reported in theHuman Gene Mutation Database in association with CMT (Stenson et al., 2014), supporting thefunctional importance of this region of the protein. We interpret H123R as a pathogenic variant.
Invitae RCV000696667 SCV000825239 pathogenic Charcot-Marie-Tooth disease, type 4A 2018-05-03 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 123 of the GDAP1 protein (p.His123Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Charcot-Marie-Tooth disease (PMID: 21753178). This variant has been observed to segregate with autosomal dominant Charcot-Marie-Tooth disease with reduced penetrance in several families, and is considered a founder mutation in the Finnish population (PMID: 21753178, 26525999, 23456260, 23963299). ClinVar contains an entry for this variant (Variation ID: 50558). Experimental studies have shown that this missense change causes an increase in mitochondrial store operated calcium entry in-vitro, suggesting a gain of protein function (PMID: 28220846). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000043549 SCV000071290 pathogenic Charcot-Marie-Tooth disease type 2K 2011-08-09 no assertion criteria provided literature only

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