Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000756940 | SCV000884932 | uncertain significance | Charcot-Marie-Tooth disease, dominant intermediate C | 2018-07-25 | criteria provided, single submitter | clinical testing | The p.Val100Met variant (rs766704849) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.001 percent (identified on 3 out of 277,194 chromosomes). The valine at position 100 is highly conserved up to worm considering 11 species (Alamut v2.10) and computational analyses of the effects of the p.Val100Met variant on protein structure and function provide conflicting results (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Val100Met variant with certainty. |
| Invitae | RCV000756940 | SCV001556560 | uncertain significance | Charcot-Marie-Tooth disease, dominant intermediate C | 2020-07-13 | criteria provided, single submitter | clinical testing | This sequence change replaces valine with methionine at codon 100 of the YARS protein (p.Val100Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs766704849, ExAC 0.003%). This variant has not been reported in the literature in individuals with YARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 618497). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Not Available; PolyPhen-2: Benign; Align-GVGD: Not Available. The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |