ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.1001T>A (p.Ile334Asn) (rs1554338262)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000653928 SCV000775818 pathogenic Charcot-Marie-Tooth disease, type 2 2017-10-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with asparagine at codon 334 of the GARS protein (p.Ile334Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of spinal muscular atrophy (Invitae). 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 and their clinical significance is uncertain. A different missense substitution at this codon (p.Ile334Phe, also reported as p.Ile280Phe) has been determined to be pathogenic (PMID: 24604904, 25168514, 17101916). This suggests that the isoleucine residue is critical for GARS protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV001334991 SCV001528013 likely pathogenic Charcot-Marie-Tooth disease type 2D 2018-10-24 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV001260980 SCV001438352 pathogenic Spinal muscular atrophy, infantile, James type 2020-10-15 no assertion criteria provided literature only

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