ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS4,PP3.

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 347 of the MME protein (p.Tyr347Cys). This variant is present in population databases (rs138218277, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 27588448). ClinVar contains an entry for this variant (Variation ID: 809558). 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. Experimental studies have shown that this missense change affects MME function (PMID: 27588448). 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.

MME: PM3, PM2:Supporting, PP1, PS3:Supporting

Identified in the heterozygous state in at least two unrelated individuals with a clinical diagnosis of Charcot-Marie-Tooth disease, and was additionally identified with an allele frequency of 0.4% in a cohort of 591 individuals with inherited polyneuropathies (PMID: 27588448); Reported previously in a patient with late onset mildly progressive demyelinating CMT who harbors another variant in the HARS1 gene. This patient's unaffected daughter is also heterozygous for the MME variant (PMID: 36517691); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27588448, 34426522, Carpenter2024[computational], 36517691, 33144514)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.054%). Protein truncation variants are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 27588448). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MME related disorder (PMID: 27588448). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

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.

PS3_moderate