7-30628598-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_002047.4(GARS1):​c.1738G>C​(p.Gly580Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G580S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GARS1
NM_002047.4 missense

Scores

17
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2U:2O:1

Conservation

PhyloP100: 9.96
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 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-30628598-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 7-30628598-G-C is Pathogenic according to our data. Variant chr7-30628598-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 9207.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-30628598-G-C is described in Lovd as [Pathogenic]. Variant chr7-30628598-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GARS1NM_002047.4 linkc.1738G>C p.Gly580Arg missense_variant Exon 14 of 17 ENST00000389266.8 NP_002038.2 P41250-1
GARS1NM_001316772.1 linkc.1576G>C p.Gly526Arg missense_variant Exon 14 of 17 NP_001303701.1 P41250-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GARS1ENST00000389266.8 linkc.1738G>C p.Gly580Arg missense_variant Exon 14 of 17 1 NM_002047.4 ENSP00000373918.3 P41250-1
GARS1ENST00000675651.1 linkc.1738G>C p.Gly580Arg missense_variant Exon 14 of 17 ENSP00000502513.1 A0A6Q8PGZ8
GARS1ENST00000675810.1 linkc.1636G>C p.Gly546Arg missense_variant Exon 13 of 16 ENSP00000502743.1 A0A6Q8PHH9
GARS1ENST00000675693.1 linkc.1570G>C p.Gly524Arg missense_variant Exon 15 of 18 ENSP00000502174.1 A0A6Q8PGA8
GARS1ENST00000675051.1 linkc.1537G>C p.Gly513Arg missense_variant Exon 14 of 17 ENSP00000502296.1 A0A6Q8PGI6
GARS1ENST00000674815.1 linkc.1369G>C p.Gly457Arg missense_variant Exon 14 of 17 ENSP00000502799.1 A0A6Q8PGW4
GARS1ENST00000674851.1 linkc.1369G>C p.Gly457Arg missense_variant Exon 15 of 18 ENSP00000502451.1 A0A6Q8PGW4
GARS1ENST00000444666.6 linkn.*159G>C non_coding_transcript_exon_variant Exon 15 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.*1452G>C non_coding_transcript_exon_variant Exon 15 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.*838G>C non_coding_transcript_exon_variant Exon 15 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.*1076G>C non_coding_transcript_exon_variant Exon 15 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.*11G>C non_coding_transcript_exon_variant Exon 13 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*1608G>C non_coding_transcript_exon_variant Exon 15 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.*11G>C non_coding_transcript_exon_variant Exon 13 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*1680G>C non_coding_transcript_exon_variant Exon 16 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.*683G>C non_coding_transcript_exon_variant Exon 14 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.*1189G>C non_coding_transcript_exon_variant Exon 14 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*1027G>C non_coding_transcript_exon_variant Exon 15 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*1170G>C non_coding_transcript_exon_variant Exon 14 of 17 ENSP00000501980.1 A0A6Q8PFU7
GARS1ENST00000676403.1 linkn.1738G>C non_coding_transcript_exon_variant Exon 14 of 16 ENSP00000502681.1 A0A6Q8PHI7
GARS1ENST00000444666.6 linkn.*159G>C 3_prime_UTR_variant Exon 15 of 18 3 ENSP00000415447.2 H7C443
GARS1ENST00000674616.1 linkn.*1452G>C 3_prime_UTR_variant Exon 15 of 18 ENSP00000502408.1 A0A6Q8PGT3
GARS1ENST00000674643.1 linkn.*838G>C 3_prime_UTR_variant Exon 15 of 17 ENSP00000501636.1 A0A6Q8PF45
GARS1ENST00000674737.1 linkn.*1076G>C 3_prime_UTR_variant Exon 15 of 18 ENSP00000502464.1 A0A6Q8PGZ9
GARS1ENST00000674807.1 linkn.*11G>C 3_prime_UTR_variant Exon 13 of 16 ENSP00000502814.1 A0A6Q8PFZ6
GARS1ENST00000675529.1 linkn.*1608G>C 3_prime_UTR_variant Exon 15 of 18 ENSP00000501655.1 A0A6Q8PFN0
GARS1ENST00000675859.1 linkn.*11G>C 3_prime_UTR_variant Exon 13 of 15 ENSP00000502033.1 A0A6Q8PFZ6
GARS1ENST00000676088.1 linkn.*1680G>C 3_prime_UTR_variant Exon 16 of 19 ENSP00000501884.1 A0A6Q8PFN0
GARS1ENST00000676140.1 linkn.*683G>C 3_prime_UTR_variant Exon 14 of 17 ENSP00000502571.1 A0A6Q8PH49
GARS1ENST00000676164.1 linkn.*1189G>C 3_prime_UTR_variant Exon 14 of 17 ENSP00000501986.1 A0A6Q8PFV5
GARS1ENST00000676210.1 linkn.*1027G>C 3_prime_UTR_variant Exon 15 of 18 ENSP00000502373.1 A0A6Q8PGN7
GARS1ENST00000676259.1 linkn.*1170G>C 3_prime_UTR_variant Exon 14 of 17 ENSP00000501980.1 A0A6Q8PFU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2Uncertain:2Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2D Uncertain:1Other:1
Jan 06, 2016
Inherited Neuropathy Consortium Ii, University Of Miami
Significance: Uncertain significance
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, Dubourg et al 2006] -

Charcot-Marie-Tooth disease type 2 Pathogenic:1
May 13, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Experimental studies have shown that this variant affects GARS protein function (PMID: 17545306, 17595294, 27008886). This sequence change replaces glycine with arginine at codon 580 of the GARS protein (p.Gly580Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with distal hereditary motor neuropathy (PMID: 12690580, 16769947). It has also been observed to segregate with disease in related individuals. This variant is also known as G526R in the literature. ClinVar contains an entry for this variant (Variation ID: 9207). For these reasons, this variant has been classified as Pathogenic. -

Neuronopathy, distal hereditary motor, type 5A Pathogenic:1
Jun 13, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Distal spinal muscular atrophy 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
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-7.8
D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.97
Gain of helix (P = 0.1736);
MVP
0.98
MPC
1.2
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.96
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs137852646; hg19: chr7-30668214; API