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

dbSNP: rs1554338260

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529259	SCV000657684	pathogenic	Charcot-Marie-Tooth disease type 2	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 334 of the GARS protein (p.Ile334Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with GARS-related conditions (PMID: 17101916, 24604904, 25476837; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as I120F and I280F. ClinVar contains an entry for this variant (Variation ID: 476747). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GARS protein function. Experimental studies have shown that this missense change affects GARS function (PMID: 25168514). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	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.
GeneDx	RCV000992024	SCV003927555	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Published functional studies show large reduction in aminoacylation activity relative to wildtype (Griffin et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25476837, 17101916, 26503042, 26138142, 25168514, 32181591, 24604904, 35332613, 31628756)
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
GeneReviews	RCV001542256	SCV001760934	not provided	Charcot-Marie-Tooth disease type 2D		no assertion provided	literature only	GARS1-HMSN (CMT2D) [James et al 2006, Griffin et al 2014]
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV001770486	SCV002011754	pathogenic	Neuronopathy, distal hereditary motor, type 5A	2021-06-22	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447145	SCV004174561	uncertain significance	Neuronopathy, distal hereditary motor, type 5	2016-01-06	no assertion criteria provided	literature only