ClinVar Miner

Submissions for variant NM_016156.5(MTMR2):c.80G>C (p.Ser27Thr) (rs879253940)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236101 SCV000292873 uncertain significance not provided 2015-05-15 criteria provided, single submitter clinical testing The c. 80 G>C variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.80 G>C may damage the natural splice donor site in intron 1 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.80 G>C variant does not effect splicing it will result in a S27T missense change. The S27T missense change is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the S27T variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000805825 SCV000945797 uncertain significance Charcot-Marie-Tooth disease type 4 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 27 of the MTMR2 protein (p.Ser27Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant also falls at the last nucleotide of exon 1 of the MTMR2 coding sequence, which is part of the consensus splice site for this exon. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with MTMR2-related disease. ClinVar contains an entry for this variant (Variation ID: 245770). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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