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):ā€‹c.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

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

GARS1
NM_002047.4 missense, splice_region

Scores

15
2
1
Splicing: ADA: 0.9889
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:2O:1

Conservation

PhyloP100: 9.89
Variant links:
Genes affected
GARS1 (HGNC:4162): (glycyl-tRNA synthetase 1) This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
Variant 7-30609729-G-C is Pathogenic according to our data. Variant chr7-30609729-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-30609729-G-C is described in Lovd as [Pathogenic]. Variant chr7-30609729-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GARS1NM_002047.4 linkc.880G>C p.Gly294Arg missense_variant, splice_region_variant Exon 7 of 17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkc.718G>C p.Gly240Arg missense_variant, splice_region_variant Exon 7 of 17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkc.880G>C p.Gly294Arg missense_variant, splice_region_variant Exon 7 of 17 1 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkc.880G>C p.Gly294Arg missense_variant, splice_region_variant Exon 7 of 17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675810.1 linkc.778G>C p.Gly260Arg missense_variant, splice_region_variant Exon 6 of 16 ENSP00000502743.1 A0A6Q8PHH9
GARS1ENST00000675693.1 linkc.712G>C p.Gly238Arg missense_variant, splice_region_variant Exon 8 of 18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkc.679G>C p.Gly227Arg missense_variant, splice_region_variant Exon 7 of 17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000674815.1 linkc.511G>C p.Gly171Arg missense_variant, splice_region_variant Exon 7 of 17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkc.511G>C p.Gly171Arg missense_variant, splice_region_variant Exon 8 of 18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000444666.6 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.*594G>C splice_region_variant, non_coding_transcript_exon_variant Exon 8 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.*218G>C splice_region_variant, non_coding_transcript_exon_variant Exon 8 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*750G>C splice_region_variant, non_coding_transcript_exon_variant Exon 8 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*822G>C splice_region_variant, non_coding_transcript_exon_variant Exon 9 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.*331G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*169G>C splice_region_variant, non_coding_transcript_exon_variant Exon 8 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*312G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkn.880G>C splice_region_variant, non_coding_transcript_exon_variant Exon 7 of 16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000674616.1 linkn.*594G>C 3_prime_UTR_variant Exon 8 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674737.1 linkn.*218G>C 3_prime_UTR_variant Exon 8 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000675529.1 linkn.*750G>C 3_prime_UTR_variant Exon 8 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000676088.1 linkn.*822G>C 3_prime_UTR_variant Exon 9 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676164.1 linkn.*331G>C 3_prime_UTR_variant Exon 7 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*169G>C 3_prime_UTR_variant Exon 8 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*312G>C 3_prime_UTR_variant Exon 7 of 17 ENSP00000501980.1 A0A6Q8PFU7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249268
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135248
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460680
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726712
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D Pathogenic:2Uncertain:1Other:1
not provided, no classification providedliterature onlyGeneReviews-GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016] -
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 01, 2003- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 13, 2025Variant 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 providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiJan 06, 2016- -
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 20, 2023The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 20, 2024This 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 submitterclinical testingGeneDxDec 18, 2023Published 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 providedliterature onlyInherited Neuropathy Consortium-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Uncertain
0.64
D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.6
D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.93
Gain of sheet (P = 0.0827);
MVP
0.90
MPC
1.2
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.99
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.90
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137852643; hg19: chr7-30649345; API