chr7-30612220-C-T

Position:

• chr7-30612220-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_002047.4(GARS1):​c.1006C>T​(p.Pro336Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P336H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.82

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-30612221-C-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 7-30612220-C-T is Pathogenic according to our data. Variant chr7-30612220-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447370.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1006C>T	p.Pro336Ser	missense_variant	8/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.844C>T	p.Pro282Ser	missense_variant	8/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1006C>T	p.Pro336Ser	missense_variant	8/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1006C>T	p.Pro336Ser	missense_variant	8/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.904C>T	p.Pro302Ser	missense_variant	7/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.838C>T	p.Pro280Ser	missense_variant	9/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.805C>T	p.Pro269Ser	missense_variant	8/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.637C>T	p.Pro213Ser	missense_variant	8/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.637C>T	p.Pro213Ser	missense_variant	9/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.1006C>T		non_coding_transcript_exon_variant	8/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*720C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.1006C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*344C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.1006C>T		non_coding_transcript_exon_variant	8/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*876C>T		non_coding_transcript_exon_variant	9/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.1006C>T		non_coding_transcript_exon_variant	8/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*948C>T		non_coding_transcript_exon_variant	10/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.1006C>T		non_coding_transcript_exon_variant	8/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*457C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*295C>T		non_coding_transcript_exon_variant	9/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*438C>T		non_coding_transcript_exon_variant	8/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1006C>T		non_coding_transcript_exon_variant	8/16			ENSP00000502681.1
GARS1	ENST00000674616.1	n.*720C>T		3_prime_UTR_variant	9/18			ENSP00000502408.1
GARS1	ENST00000674737.1	n.*344C>T		3_prime_UTR_variant	9/18			ENSP00000502464.1
GARS1	ENST00000675529.1	n.*876C>T		3_prime_UTR_variant	9/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*948C>T		3_prime_UTR_variant	10/19			ENSP00000501884.1
GARS1	ENST00000676164.1	n.*457C>T		3_prime_UTR_variant	8/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*295C>T		3_prime_UTR_variant	9/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*438C>T		3_prime_UTR_variant	8/17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro336 amino acid residue in GARS. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GARS protein function. ClinVar contains an entry for this variant (Variation ID: 447370). This variant has not been reported in the literature in individuals affected with GARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 336 of the GARS protein (p.Pro336Ser). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 28, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.92	D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.80		Gain of phosphorylation at P336 (P = 0.0369);
MVP		0.88
MPC		1.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs1554338264; hg19: chr7-30651836;