ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.715C>T (p.Leu239Phe) (rs104894080)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414821 SCV000492715 pathogenic Elevated serum creatine phosphokinase; Sensory neuropathy; Polyneuropathy; Elevated alkaline phosphatase; Peripheral axonal neuropathy 2015-11-02 criteria provided, single submitter clinical testing
GeneDx RCV000439841 SCV000513131 pathogenic not provided 2016-11-11 criteria provided, single submitter clinical testing The L239F variant in the GDAP1 gene has been reported previously in association with autosomal recessive Charcot-Marie-Tooth (CMT) (Ammar et al., 2003; Kabzinska et al., 2010; Moroni et al., 2009; Baránková et al., 2007). The L239F variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. 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. Additionally, missense variants in nearby residues (W238C; C240Y) have been reported in the Human Gene Mutation Database in association with autosomal recessive Charcot-Marie-Tooth disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, L239F is considered a pathogenic variant.
GeneReviews RCV000034153 SCV000058090 pathologic Charcot-Marie-Tooth disease, type 4A 2013-02-28 no assertion criteria provided curation Converted during submission to Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779562 SCV000916236 pathogenic GDAP1-Related Disorders 2018-09-20 criteria provided, single submitter clinical testing The GDAP1 c.715C>T (p.Leu239Phe) missense variant has been reported in at least six studies and is found in a total of 21 probands with autosomal recessive Charcot-Marie-Tooth disease (CMT), including five in a homozygous state, 15 in a compound heterozygous state, and one in a heterozygous state without a second variant identified (Ammar et al. 2003, Kabzinska et al. 2003, Barankova et al. 2007, Auer-Grumbach et al. 2008, Moroni et al. 2009, Kabzinska et al. 2010). Ammar et al. (2003) identified the c.715C>T (p.Leu239Phe) variant in a compound heterozygous state with a frameshift variant in two siblings with CMT. Their unaffected mother carried the p.Leu239Phe variant and their unaffected father carried the frameshift variant. The p.Leu239Phe variant was absent from 158 controls and is reported at a frequency of 0.000071 in the European (non-Finnish) population of the Genome Aggregation Database. Haplotype analysis suggests that the p.Leu239Phe variant is likely a founder mutation in the central and eastern European population (Kabzinska et al. 2010). Based on the collective evidence, the p.Leu239Phe variant classified as pathogenic for GDAP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Inherited Neuropathy Consortium RCV000789780 SCV000929164 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Institute of Human Genetics,Cologne University RCV000004420 SCV000787764 pathogenic Charcot-Marie-Tooth disease, recessive intermediate A 2018-04-25 no assertion criteria provided clinical testing
Invitae RCV000034153 SCV000947042 pathogenic Charcot-Marie-Tooth disease, type 4A 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 239 of the GDAP1 protein (p.Leu239Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs104894080, ExAC 0.006%). This variant has been observed to segregate with autosomal recessive Charcot-Marie-Tooth disease in several families (PMID: 14561495, 18504680, 19500985, 20232219) and has been reported in additional, unrelated affected individuals (PMID: 17433678, 25231362, 18991200).  It has been described as a founder mutation in the European population (PMID: 20232219). ClinVar contains an entry for this variant (Variation ID: 4200). 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: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004420 SCV000024593 pathogenic Charcot-Marie-Tooth disease, recessive intermediate A 2010-07-01 no assertion criteria provided literature only
OMIM RCV000033147 SCV000056929 pathogenic Charcot-Marie-Tooth disease type 2K 2010-07-01 no assertion criteria provided literature only

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