ClinVar Miner

Submissions for variant NM_007289.4(MME):c.1948G>A (p.Ala650Thr)

gnomAD frequency: 0.00001  dbSNP: rs778011002
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002026830 SCV002314048 uncertain significance not provided 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 650 of the MME protein (p.Ala650Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MME-related conditions. 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"). 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.
Molecular Genetics, Royal Melbourne Hospital RCV005250233 SCV005900457 uncertain significance Charcot-Marie-Tooth disease 2024-09-08 criteria provided, single submitter clinical testing This sequence change in MME is predicted to replace alanine with threonine at codon 650, p.(Ala650Thr). The Ala650 residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the peptidase domain. Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.929). The highest population minor allele frequency in the population database gnomAD v4.1 is 0.001% (13/1,179,466 alleles) in the non-Finnish European, consistent with late-onset autosomal dominant disease. The variant has been observed in at least two with neuropathy (Royal Melbourne Hospital; Invitae personal correspondence). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3, PS4_supporting.

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