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

Total submissions: 9

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.
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.
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
GeneReviews	RCV000034153	SCV000058090	pathologic	Charcot-Marie-Tooth disease, type 4A	2013-02-28	no assertion criteria provided	curation	Converted during submission to Pathogenic.
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
Inherited Neuropathy Consortium	RCV000789780	SCV000929164	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only