Submissions for variant NM_004990.4(MARS1):c.2053G>A (p.Val685Ile) (rs558631075)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000526373	SCV000655631	uncertain significance	Interstitial lung and liver disease; Charcot-Marie-Tooth disease, axonal, type 2u	2017-08-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine with isoleucine at codon 685 of the MARS protein (p.Val685Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MARS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002141	SCV001159996	uncertain significance	not specified	2018-10-09	criteria provided, single submitter	clinical testing	The MARS c.2053G>A; p.Val685Ile variant (rs558631075), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 475418). This variant is found in the general population with an overall allele frequency of 0.001% (4/277,206 alleles) in the Genome Aggregation Database. The valine at codon 685 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Val685Ile variant is uncertain at this time.

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