7-30628598-G-C

Position:

• chr7-30628598-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2 O:1
• Conservation: PhyloP100: 9.96

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]

GARS1 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1738G>C	p.Gly580Arg	missense_variant	14/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1576G>C	p.Gly526Arg	missense_variant	14/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1738G>C	p.Gly580Arg	missense_variant	14/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1738G>C	p.Gly580Arg	missense_variant	14/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1636G>C	p.Gly546Arg	missense_variant	13/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1570G>C	p.Gly524Arg	missense_variant	15/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1537G>C	p.Gly513Arg	missense_variant	14/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1369G>C	p.Gly457Arg	missense_variant	14/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1369G>C	p.Gly457Arg	missense_variant	15/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*159G>C		non_coding_transcript_exon_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1452G>C		non_coding_transcript_exon_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*838G>C		non_coding_transcript_exon_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1076G>C		non_coding_transcript_exon_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*11G>C		non_coding_transcript_exon_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1608G>C		non_coding_transcript_exon_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*11G>C		non_coding_transcript_exon_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1680G>C		non_coding_transcript_exon_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*683G>C		non_coding_transcript_exon_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1189G>C		non_coding_transcript_exon_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1027G>C		non_coding_transcript_exon_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1170G>C		non_coding_transcript_exon_variant	14/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1738G>C		non_coding_transcript_exon_variant	14/16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*159G>C		3_prime_UTR_variant	15/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1452G>C		3_prime_UTR_variant	15/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*838G>C		3_prime_UTR_variant	15/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1076G>C		3_prime_UTR_variant	15/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*11G>C		3_prime_UTR_variant	13/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1608G>C		3_prime_UTR_variant	15/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*11G>C		3_prime_UTR_variant	13/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1680G>C		3_prime_UTR_variant	16/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*683G>C		3_prime_UTR_variant	14/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1189G>C		3_prime_UTR_variant	14/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1027G>C		3_prime_UTR_variant	15/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1170G>C		3_prime_UTR_variant	14/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	GARS1-HMSN (CMT2D) [Antonellis et al 2003, Dubourg et al 2006] -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 13, 2021

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). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects GARS protein function (PMID: 17545306, 17595294, 27008886). 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). -

Neuronopathy, distal hereditary motor, type 5A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 13, 2006

- -

Distal spinal muscular atrophy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

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

Other links and lift over

dbSNP: rs137852646; hg19: chr7-30668214;