Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000700463 | SCV000829220 | pathogenic | Charcot-Marie-Tooth disease, type I | 2023-11-15 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 224 of the MPZ protein (p.Asp224Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 16488608, 19259128, 19882637, 21149811, 27088055). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41024). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MPZ function (PMID: 31173589). For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV002362608 | SCV002665020 | likely pathogenic | Inborn genetic diseases | 2021-04-23 | criteria provided, single submitter | clinical testing | The p.D224Y variant (also known as c.670G>T), located in coding exon 6 of the MPZ gene, results from a G to T substitution at nucleotide position 670. The aspartic acid at codon 224 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was detected as heterozygous in multiple unrelated individuals with a consistent disease phenotype that includes sensory deficits, pes cavus, diminished nerve conduction velocities, and absent or diminished reflexes (Fabrizi GM et al. Neuromuscul Disord, 2006 Mar;16:183-7; Miltenberger-Miltenyi G et al. Eur J Hum Genet, 2009 Sep;17:1154-9; Benedetti S et al. Arch Neurol, 2010 Dec;67:1498-505; Schneider-Gold C et al. Muscle Nerve, 2010 Apr;41:550-4). In the heterozygous state, this alteration segregated with disease in one family (Schneider-Gold C et al. Muscle Nerve, 2010 Apr;41:550-4). This variant was also detected as homozygous in two affected individuals in the same family (Fabrizi GM et al. Neuromuscul Disord, 2006 Mar;16:183-7). Biochemical and structural analyses suggest that this alteration leads to structural changes that can contribute to hypermyelination (Raasakka A et al. PLoS One, 2019 Jun;14:e0216833). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
OMIM | RCV000033921 | SCV000035524 | pathogenic | Charcot-Marie-Tooth disease type 1B | 2006-03-01 | no assertion criteria provided | literature only | |
Gene |
RCV000033921 | SCV000057838 | not provided | Charcot-Marie-Tooth disease type 1B | no assertion provided | literature only | ||
Inherited Neuropathy Consortium | RCV000789431 | SCV000928786 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |