ClinVar Miner

Submissions for variant NM_001605.2(AARS1):c.497T>G (p.Ile166Ser) (rs199997425)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204212 SCV000262331 uncertain significance Charcot-Marie-Tooth disease, type 2 2016-01-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 166 of the AARS protein (p.Ile166Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. This variant is present in population databases (rs199997425, ExAC 0.03%). This variant has been reported in an individual affected with Charcot-Marie-Tooth neuropathy type 1 (PMID: 25025039). However, homozygous pathogenic allele was identified in the SH3TC2 gene, which suggests that this c.497T>G substitution in AARS was not the primary cause of disease in this individual. Variants in AARS are associated with Charcot-Marie-Tooth neuropathy type 2 autosomal dominant form and SH3TC2 is associated with Charcot-Marie-Tooth neuropathy type 1 autosomal recessive form and it is uncertain whether (p.Ile166Ser) in AARS gene contributed to the phenotype in this individual affected with Charcot-Marie-Tooth neuropathy type 1. ClinVar contains an entry for this variant (Variation ID: 157537). 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 disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept. of Medical Genetics, Telemark Hospital Trust RCV000144883 SCV000118594 uncertain significance Charcot-Marie-Tooth disease 2013-11-01 no assertion criteria provided research

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