ClinVar

Description

Variant summary: MME c.1040A>G (p.Tyr347Cys) results in a non-conservative amino acid change located in the Peptidase M13, N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251266 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, suggesting it is unlikely to be associated with a highly penetrant autosomal dominant condition. c.1040A>G has been reported in the literature in the heterozygous state in at least two individuals with Charcot-Marie Disease Axonal Type 2T who had a positive family history, and also in individuals affected with late onset polyneuropathy, including an individual who also had a putative pathogenic variant in the HARS1 gene and whose daughter carried the variant and was unaffected, but was below the age of disease onset observed in the family (e.g. Auer-Grumbach_2016, Senderek_2020, Parisi_2023). The c.1040A>G variant has also been reported in the homozgous state in two siblings who were both affected with late onset axonal neuropathy, however a third affected sibling was only heterozygous for the variant and both parents, who were obligate heterozygotes, were unaffected (Senderek_2020). The variant has also been reported in cohorts of individuals of similar ancestry without polyneuropathies (Auer-Grumbach_2016, Senderek_2020). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Axonal Type 2T. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found that the variant exhibits approximately 60-65% activity of the wild type protein (Auer-Grumbach_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27588448, 33144514, 36517691). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.