Submissions for variant NM_002047.4(GARS1):c.1359+1G>A

gnomAD frequency: 0.00001  dbSNP: rs868796615

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236152	SCV000293171	likely pathogenic	not provided	2025-03-20	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25168514, 26138142, 26503042)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003743689	SCV004558178	uncertain significance	Charcot-Marie-Tooth disease type 2	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 10 of the GARS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in GARS cause disease. This variant is not present in population databases (gnomAD no frequency). 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: 245951). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.