7-30612215-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002047.4(GARS1):c.1001T>C(p.Ile334Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I334M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

GARS1
NM_002047.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.93

Publications

0 publications found

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]

GARS1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease type 2D
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, type 5A
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
spinal muscular atrophy, infantile, James type
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

GARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002047.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-30612216-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 931791.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 7-30612215-T-C is Pathogenic according to our data. Variant chr7-30612215-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 958512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4 link	c.1001T>C	p.Ile334Thr	missense_variant	Exon 8 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1 link	c.839T>C	p.Ile280Thr	missense_variant	Exon 8 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GARS1	ENST00000389266.8 link	c.1001T>C	p.Ile334Thr	missense_variant	Exon 8 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1 link	c.1001T>C	p.Ile334Thr	missense_variant	Exon 8 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1 link	c.899T>C	p.Ile300Thr	missense_variant	Exon 7 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1 link	c.833T>C	p.Ile278Thr	missense_variant	Exon 9 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1 link	c.800T>C	p.Ile267Thr	missense_variant	Exon 8 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 8 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1 link	c.632T>C	p.Ile211Thr	missense_variant	Exon 9 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1 link	n.*715T>C		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1 link	n.*339T>C		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1 link	n.*871T>C		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1 link	n.*943T>C		non_coding_transcript_exon_variant	Exon 10 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1 link	n.*452T>C		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*290T>C		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*433T>C		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1 link	n.1001T>C		non_coding_transcript_exon_variant	Exon 8 of 16			ENSP00000502681.1
GARS1	ENST00000674616.1 link	n.*715T>C		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502408.1
GARS1	ENST00000674737.1 link	n.*339T>C		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502464.1
GARS1	ENST00000675529.1 link	n.*871T>C		3_prime_UTR_variant	Exon 9 of 18			ENSP00000501655.1
GARS1	ENST00000676088.1 link	n.*943T>C		3_prime_UTR_variant	Exon 10 of 19			ENSP00000501884.1
GARS1	ENST00000676164.1 link	n.*452T>C		3_prime_UTR_variant	Exon 8 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1 link	n.*290T>C		3_prime_UTR_variant	Exon 9 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1 link	n.*433T>C		3_prime_UTR_variant	Exon 8 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2

Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the GARS protein (p.Ile334Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant Charcot-Marie-Tooth disease (internal data). ClinVar contains an entry for this variant (Variation ID: 958512). 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%. This variant disrupts the p.Ile334 amino acid residue in GARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17101916, 24604904, 25168514, 25476837). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

not provided

Pathogenic:1

Jan 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM1, PM2, PM5

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.59

PhyloP100

7.9

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.94

ClinPred

1.0

GERP RS

5.6

Varity_R

0.93

gMVP

0.85

Mutation Taster

=17/83

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over