ClinVar Miner

Submissions for variant NM_018972.4(GDAP1):c.399G>A (p.Met133Ile) (rs139808557)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767009 SCV000292559 uncertain significance not provided 2016-07-13 criteria provided, single submitter clinical testing The M133I variant has been reported previously in an individual with suspected autosomal dominant CMT1 (Antoniadi et al., 2015). The M133I 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, but it has been observed in the heterozygous state in multiple unaffected adults tested at GeneDx. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (D129H, S130C) have been reported in the Human Gene Mutation Database in association with CMT (Stenson et al., 2014). However, the M133I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000474009 SCV000544594 pathogenic Charcot-Marie-Tooth disease, type 4A 2019-11-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 133 of the GDAP1 protein (p.Met133Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs139808557, ExAC 0.01%). This variant has been observed in combination with another GDAP1 variant in individual(s) with peripheral neuropathy (Invitae). It has also been observed to segregate with disease in related individuals. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 245607). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000236408 SCV000613471 uncertain significance not specified 2017-01-30 criteria provided, single submitter clinical testing

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