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
Consequence
NM_002047.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GARS1 | ENST00000389266.8 | c.1738G>C | p.Gly580Arg | missense_variant | Exon 14 of 17 | 1 | NM_002047.4 | ENSP00000373918.3 | ||
GARS1 | ENST00000675651.1 | c.1738G>C | p.Gly580Arg | missense_variant | Exon 14 of 17 | ENSP00000502513.1 | ||||
GARS1 | ENST00000675810.1 | c.1636G>C | p.Gly546Arg | missense_variant | Exon 13 of 16 | ENSP00000502743.1 | ||||
GARS1 | ENST00000675693.1 | c.1570G>C | p.Gly524Arg | missense_variant | Exon 15 of 18 | ENSP00000502174.1 | ||||
GARS1 | ENST00000675051.1 | c.1537G>C | p.Gly513Arg | missense_variant | Exon 14 of 17 | ENSP00000502296.1 | ||||
GARS1 | ENST00000674815.1 | c.1369G>C | p.Gly457Arg | missense_variant | Exon 14 of 17 | ENSP00000502799.1 | ||||
GARS1 | ENST00000674851.1 | c.1369G>C | p.Gly457Arg | missense_variant | Exon 15 of 18 | ENSP00000502451.1 | ||||
GARS1 | ENST00000444666.6 | n.*159G>C | non_coding_transcript_exon_variant | Exon 15 of 18 | 3 | ENSP00000415447.2 | ||||
GARS1 | ENST00000674616.1 | n.*1452G>C | non_coding_transcript_exon_variant | Exon 15 of 18 | ENSP00000502408.1 | |||||
GARS1 | ENST00000674643.1 | n.*838G>C | non_coding_transcript_exon_variant | Exon 15 of 17 | ENSP00000501636.1 | |||||
GARS1 | ENST00000674737.1 | n.*1076G>C | non_coding_transcript_exon_variant | Exon 15 of 18 | ENSP00000502464.1 | |||||
GARS1 | ENST00000674807.1 | n.*11G>C | non_coding_transcript_exon_variant | Exon 13 of 16 | ENSP00000502814.1 | |||||
GARS1 | ENST00000675529.1 | n.*1608G>C | non_coding_transcript_exon_variant | Exon 15 of 18 | ENSP00000501655.1 | |||||
GARS1 | ENST00000675859.1 | n.*11G>C | non_coding_transcript_exon_variant | Exon 13 of 15 | ENSP00000502033.1 | |||||
GARS1 | ENST00000676088.1 | n.*1680G>C | non_coding_transcript_exon_variant | Exon 16 of 19 | ENSP00000501884.1 | |||||
GARS1 | ENST00000676140.1 | n.*683G>C | non_coding_transcript_exon_variant | Exon 14 of 17 | ENSP00000502571.1 | |||||
GARS1 | ENST00000676164.1 | n.*1189G>C | non_coding_transcript_exon_variant | Exon 14 of 17 | ENSP00000501986.1 | |||||
GARS1 | ENST00000676210.1 | n.*1027G>C | non_coding_transcript_exon_variant | Exon 15 of 18 | ENSP00000502373.1 | |||||
GARS1 | ENST00000676259.1 | n.*1170G>C | non_coding_transcript_exon_variant | Exon 14 of 17 | ENSP00000501980.1 | |||||
GARS1 | ENST00000676403.1 | n.1738G>C | non_coding_transcript_exon_variant | Exon 14 of 16 | ENSP00000502681.1 | |||||
GARS1 | ENST00000444666.6 | n.*159G>C | 3_prime_UTR_variant | Exon 15 of 18 | 3 | ENSP00000415447.2 | ||||
GARS1 | ENST00000674616.1 | n.*1452G>C | 3_prime_UTR_variant | Exon 15 of 18 | ENSP00000502408.1 | |||||
GARS1 | ENST00000674643.1 | n.*838G>C | 3_prime_UTR_variant | Exon 15 of 17 | ENSP00000501636.1 | |||||
GARS1 | ENST00000674737.1 | n.*1076G>C | 3_prime_UTR_variant | Exon 15 of 18 | ENSP00000502464.1 | |||||
GARS1 | ENST00000674807.1 | n.*11G>C | 3_prime_UTR_variant | Exon 13 of 16 | ENSP00000502814.1 | |||||
GARS1 | ENST00000675529.1 | n.*1608G>C | 3_prime_UTR_variant | Exon 15 of 18 | ENSP00000501655.1 | |||||
GARS1 | ENST00000675859.1 | n.*11G>C | 3_prime_UTR_variant | Exon 13 of 15 | ENSP00000502033.1 | |||||
GARS1 | ENST00000676088.1 | n.*1680G>C | 3_prime_UTR_variant | Exon 16 of 19 | ENSP00000501884.1 | |||||
GARS1 | ENST00000676140.1 | n.*683G>C | 3_prime_UTR_variant | Exon 14 of 17 | ENSP00000502571.1 | |||||
GARS1 | ENST00000676164.1 | n.*1189G>C | 3_prime_UTR_variant | Exon 14 of 17 | ENSP00000501986.1 | |||||
GARS1 | ENST00000676210.1 | n.*1027G>C | 3_prime_UTR_variant | Exon 15 of 18 | ENSP00000502373.1 | |||||
GARS1 | ENST00000676259.1 | n.*1170G>C | 3_prime_UTR_variant | Exon 14 of 17 | ENSP00000501980.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2D Uncertain:1Other:1
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GARS1-HMSN (CMT2D) [Antonellis et al 2003, Dubourg et al 2006] -
Charcot-Marie-Tooth disease type 2 Pathogenic:1
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
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Distal spinal muscular atrophy Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at