Submissions for variant NM_002047.4(GARS1):c.1694T>A (p.Leu565Gln)

gnomAD frequency: 0.00004  dbSNP: rs200726600

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035448	SCV001198775	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 565 of the GARS protein (p.Leu565Gln). This variant is present in population databases (rs200726600, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 834709). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function with a negative predictive value of 95%. 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.
Illumina Laboratory Services, Illumina	RCV001161101	SCV001322947	benign	Neuronopathy, distal hereditary motor, type 5A	2017-07-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001161102	SCV001322948	benign	Distal spinal muscular atrophy	2017-07-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001162652	SCV001324613	uncertain significance	Charcot-Marie-Tooth disease type 2D	2017-07-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV004030955	SCV002755008	uncertain significance	not specified	2019-12-18	criteria provided, single submitter	clinical testing	The p.L565Q variant (also known as c.1694T>A), located in coding exon 13 of the GARS gene, results from a T to A substitution at nucleotide position 1694. The leucine at codon 565 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736961	SCV004562322	uncertain significance	not provided	2023-03-02	criteria provided, single submitter	clinical testing	The GARS1 c.1694T>A; p.Leu565Gln variant (rs200726600), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 834709). This variant is found in the non-Finnish European population with an allele frequency of 0.006% (7/127,474 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.42). Due to limited information, the clinical significance of this variant is uncertain at this time.