Submissions for variant NM_002047.4(GARS1):c.52C>A (p.Leu18Met)

gnomAD frequency: 0.00003  dbSNP: rs368574634

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001236766	SCV001409502	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-06-21	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 18 of the GARS protein (p.Leu18Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 962841). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987805	SCV004803786	uncertain significance	not specified	2024-01-03	criteria provided, single submitter	clinical testing	Variant summary: GARS1 c.52C>A (p.Leu18Met) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 1595172 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.52C>A in individuals affected with GARS1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.