Submissions for variant NM_007289.4(MME):c.1520A>G (p.Tyr507Cys)

gnomAD frequency: 0.00001  dbSNP: rs367899772

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002030564	SCV002272809	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MME-related conditions. ClinVar contains an entry for this variant (Variation ID: 1486041). This variant is present in population databases (rs367899772, gnomAD 0.0009%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 507 of the MME protein (p.Tyr507Cys). 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.
Ambry Genetics	RCV003170394	SCV003904757	uncertain significance	Inborn genetic diseases	2023-02-23	criteria provided, single submitter	clinical testing	The c.1520A>G (p.Y507C) alteration is located in exon 16 (coding exon 15) of the MME gene. This alteration results from a A to G substitution at nucleotide position 1520, causing the tyrosine (Y) at amino acid position 507 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Molecular Genetics, Royal Melbourne Hospital	RCV003994372	SCV004812720	uncertain significance	MME-related autosomal dominant Charcot Marie Tooth disease type 2	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in MME is predicted to replace tyrosine with cysteine at codon 507, p.(Tyr507Cys). The tyrosine residue is highly conserved (100 vertebrates, UCSC), and is located in the peptidase M13 domain. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/113,402 alleles) in the European (non-Finnish) population, which is consistent with MME-neuropathy. This variant has been reported in multiple individuals with a phenotype consistent with MME-neuropathy (PMID: 33144514; Invitae personal communication). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.888). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, PP3, PS4_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782845	SCV005394135	uncertain significance	not specified	2024-09-03	criteria provided, single submitter	clinical testing	Variant summary: MME c.1520A>G (p.Tyr507Cys) results in a non-conservative amino acid change in 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 8e-06 in 250794 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1520A>G in individuals affected with Charcot-Marie Disease Axonal Type 2T and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1486041). Based on the evidence outlined above, the variant was classified as uncertain significance.