ClinVar Miner

Submissions for variant NM_002047.4(GARS1):c.1000A>T (p.Ile334Phe) (rs1554338260)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529259 SCV000657684 pathogenic Charcot-Marie-Tooth disease, type 2 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 334 of the GARS protein (p.Ile334Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with GARS-related neuropathy in a single family (PMID: 24604904) and has been reported in an individual affected with distal hereditary motor neuropathy (PMID: 17101916) and another with Charcot-Marie-Tooth disease (PMID: 25476837). This variant is also known as I120F and I280F in the literature. Experimental studies have shown that this missense change severely impairs tRNA charging (<10% compared with wild type) in vitro (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000992024 SCV001143983 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/280908 chr). Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease in affected individuals from a single family.
Inherited Neuropathy Consortium RCV000789773 SCV000929157 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000790255 SCV000929655 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only

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