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

dbSNP: rs1554338262

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000653928	SCV000775818	pathogenic	Charcot-Marie-Tooth disease type 2	2022-06-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile334 amino acid residue in GARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17101916, 24604904, 25168514). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 543227). This missense change has been observed in individual(s) with clinical features of spinal muscular atrophy (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 334 of the GARS protein (p.Ile334Asn).
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
GeneReviews	RCV001260980	SCV001760935	not provided	Spinal muscular atrophy, infantile, James type		no assertion provided	literature only	GARS1-iSMA [Markovitz et al 2020]