Submissions for variant NM_004990.4(MARS1):c.699T>G (p.Ile233Met) (rs201597392)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523299	SCV000618076	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing	The I233M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The I233M variant is observed in 2/6614 alleles from individuals of Finnish background, in the ExAC dataset (Lek et al., 2016). The I233M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000652554	SCV000774424	uncertain significance	Interstitial lung and liver disease; Charcot-Marie-Tooth disease, axonal, type 2u	2017-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with methionine at codon 233 of the MARS protein (p.Ile233Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs201597392, ExAC 0.03%). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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