Submissions for variant NM_018972.4(GDAP1):c.399G>A (p.Met133Ile)

gnomAD frequency: 0.00017  dbSNP: rs139808557

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767009	SCV000292559	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14702039, 26392352, 32376792)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000474009	SCV000544594	pathogenic	Charcot-Marie-Tooth disease type 4A	2024-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 133 of the GDAP1 protein (p.Met133Ile). This variant is present in population databases (rs139808557, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Charcot-Marie-Tooth disease (PMID: 26392352, 32376792; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 245607). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GDAP1 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000767009	SCV000613471	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401192	SCV004122513	uncertain significance	not specified	2023-10-04	criteria provided, single submitter	clinical testing	Variant summary: GDAP1 c.399G>A (p.Met133Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251478 control chromosomes. c.399G>A has been reported in the literature in at least one individual affected with Charcot-Marie Disease type 4A, without a reported second variant (e.g. Antoniadi_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26392352). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004020916	SCV004874622	likely pathogenic	Inborn genetic diseases	2023-10-24	criteria provided, single submitter	clinical testing	The c.399G>A (p.M133I) alteration is located in exon 3 (coding exon 3) of the GDAP1 gene. This alteration results from a G to A substitution at nucleotide position 399, causing the methionine (M) at amino acid position 133 to be replaced by an isoleucine (I)._x000D_ _x000D_ Based on the available evidence, the c.399G>A (p.M133I) alteration alteration is classified as likely pathogenic for autosomal recessive GDAP1-related Charcot-Marie-Tooth disease; however, it is unlikely to be causative of autosomal dominant GDAP1-related Charcot-Marie-Tooth disease, type 2. Based on data from gnomAD, the A allele has an overall frequency of 0.011% (31/282872) total alleles studied. The highest observed frequency was 0.024% (31/129184) of European (non-Finnish) alleles. This alteration was detected in conjunction with another alteration in GDAP1, in multiple individuals with features consistent with GDAP1-related Charcot-Marie-Tooth disease (external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000767009	SCV005409478	uncertain significance	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005044489	SCV005679122	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2K; Charcot-Marie-Tooth disease type 4A; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive; Charcot-Marie-Tooth disease recessive intermediate A	2024-01-17	criteria provided, single submitter	clinical testing