7-30609729-G-C

Variant names:

• chr7-30609729-G-C
• rs137852643
• NM_002047.4:c.880G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_002047.4(GARS1):​c.880G>C​(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 (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense, splice_region
• Scores: Splicing: ADA: 0.9889
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:2 O:1
• Conservation: PhyloP100: 9.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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
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: 1 AN: 249268 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135248

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

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:5 Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D Pathogenic:2 Uncertain:1 Other:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

GARS1-HMSN (CMT2D) [Antonellis et al 2003, He et al 2015, Malissovas et al 2016] -

not specified Pathogenic:1

Nov 20, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Other links and lift over

dbSNP: rs137852643; hg19: chr7-30649345;