7-30609729-G-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002047.4(GARS1):āc.880G>Cā(p.Gly294Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_002047.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GARS1 | NM_002047.4 | c.880G>C | p.Gly294Arg | missense_variant, splice_region_variant | Exon 7 of 17 | ENST00000389266.8 | NP_002038.2 | |
GARS1 | NM_001316772.1 | c.718G>C | p.Gly240Arg | missense_variant, splice_region_variant | Exon 7 of 17 | NP_001303701.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GARS1 | ENST00000389266.8 | c.880G>C | p.Gly294Arg | missense_variant, splice_region_variant | Exon 7 of 17 | 1 | NM_002047.4 | ENSP00000373918.3 | ||
GARS1 | ENST00000675651.1 | c.880G>C | p.Gly294Arg | missense_variant, splice_region_variant | Exon 7 of 17 | ENSP00000502513.1 | ||||
GARS1 | ENST00000675810.1 | c.778G>C | p.Gly260Arg | missense_variant, splice_region_variant | Exon 6 of 16 | ENSP00000502743.1 | ||||
GARS1 | ENST00000675693.1 | c.712G>C | p.Gly238Arg | missense_variant, splice_region_variant | Exon 8 of 18 | ENSP00000502174.1 | ||||
GARS1 | ENST00000675051.1 | c.679G>C | p.Gly227Arg | missense_variant, splice_region_variant | Exon 7 of 17 | ENSP00000502296.1 | ||||
GARS1 | ENST00000674815.1 | c.511G>C | p.Gly171Arg | missense_variant, splice_region_variant | Exon 7 of 17 | ENSP00000502799.1 | ||||
GARS1 | ENST00000674851.1 | c.511G>C | p.Gly171Arg | missense_variant, splice_region_variant | Exon 8 of 18 | ENSP00000502451.1 | ||||
GARS1 | ENST00000444666.6 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 18 | 3 | ENSP00000415447.2 | ||||
GARS1 | ENST00000674616.1 | n.*594G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 8 of 18 | ENSP00000502408.1 | |||||
GARS1 | ENST00000674643.1 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 17 | ENSP00000501636.1 | |||||
GARS1 | ENST00000674737.1 | n.*218G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 8 of 18 | ENSP00000502464.1 | |||||
GARS1 | ENST00000674807.1 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 16 | ENSP00000502814.1 | |||||
GARS1 | ENST00000675529.1 | n.*750G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 8 of 18 | ENSP00000501655.1 | |||||
GARS1 | ENST00000675859.1 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 15 | ENSP00000502033.1 | |||||
GARS1 | ENST00000676088.1 | n.*822G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 9 of 19 | ENSP00000501884.1 | |||||
GARS1 | ENST00000676140.1 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 17 | ENSP00000502571.1 | |||||
GARS1 | ENST00000676164.1 | n.*331G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 17 | ENSP00000501986.1 | |||||
GARS1 | ENST00000676210.1 | n.*169G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 8 of 18 | ENSP00000502373.1 | |||||
GARS1 | ENST00000676259.1 | n.*312G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 17 | ENSP00000501980.1 | |||||
GARS1 | ENST00000676403.1 | n.880G>C | splice_region_variant, non_coding_transcript_exon_variant | Exon 7 of 16 | ENSP00000502681.1 | |||||
GARS1 | ENST00000674616.1 | n.*594G>C | 3_prime_UTR_variant | Exon 8 of 18 | ENSP00000502408.1 | |||||
GARS1 | ENST00000674737.1 | n.*218G>C | 3_prime_UTR_variant | Exon 8 of 18 | ENSP00000502464.1 | |||||
GARS1 | ENST00000675529.1 | n.*750G>C | 3_prime_UTR_variant | Exon 8 of 18 | ENSP00000501655.1 | |||||
GARS1 | ENST00000676088.1 | n.*822G>C | 3_prime_UTR_variant | Exon 9 of 19 | ENSP00000501884.1 | |||||
GARS1 | ENST00000676164.1 | n.*331G>C | 3_prime_UTR_variant | Exon 7 of 17 | ENSP00000501986.1 | |||||
GARS1 | ENST00000676210.1 | n.*169G>C | 3_prime_UTR_variant | Exon 8 of 18 | ENSP00000502373.1 | |||||
GARS1 | ENST00000676259.1 | n.*312G>C | 3_prime_UTR_variant | Exon 7 of 17 | ENSP00000501980.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249268Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135248
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460680Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726712
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2D Pathogenic:2Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016] - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2025 | Variant summary: GARS1 c.880G>C (p.Gly294Arg) results in a non-conservative amino acid change located in the GlyRS-like_core domain (IPR033731) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249268 control chromosomes. c.880G>C has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease type 2D (example, Sivakumar_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in completely disruption of heterodimer formation in N2a cells (Nangle_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17595294, 16014653). ClinVar contains an entry for this variant (Variation ID: 9204). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2023 | The c.880G>C (p.G294R) alteration is located in exon 7 (coding exon 7) of the GARS gene. This alteration results from a G to C substitution at nucleotide position 880, causing the glycine (G) at amino acid position 294 to be replaced by an arginine (R)._x000D_ _x000D_ for autosomal dominant GARS1-related axonal neuropathy; however, its clinical significance for autosomal recessive Cytoplasmic and mitochondrial glycyl-tRNA synthetase deficiency is uncertain. Based on data from gnomAD, the C allele has an overall frequency of <0.001% (1/249268) total alleles studied. The highest observed frequency was 0.001% (1/113114) of European (non-Finnish) alleles. This alteration has been detected in the heterozygous state in multiple individuals with clinical features of GARS1-related axonal neuropathy (Antonellis, 2003; External communication). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, G294R is deleterious and is highly destabilizing to the local structure (Ambry internal data). In multiple assays testing GARS function, this variant showed functionally abnormal results (Antonellis, 2006; Nangle, 2007; He, 2011; He, 2015; Niehues, 2015; Malissovas, 2016; Mo, 2018; Cui, 2023). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 20, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 294 of the GARS protein (p.Gly294Arg). This variant is present in population databases (rs137852643, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 8872480, 10732809, 12690580; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9204). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GARS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GARS function (PMID: 17035524, 17595294, 21737751, 26138142, 26503042, 27008886). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2023 | Published functional studies demonstrate impaired enzyme activity, dimer instability, and inappropriate ligand binding (PMID: 17595294, 21737751, 26503042); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10732809, 21737751, 25168514, 25476837, 17595294, 17035524, 8872480, 26503042, 27008886, 29520015, 12690580) - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at