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NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr) AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 11, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003987472.2

Allele description [Variation Report for NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)]

NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)

Gene:
MARS1:methionyl-tRNA synthetase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q13.3
Genomic location:
Preferred name:
NM_004990.4(MARS1):c.1177G>A (p.Ala393Thr)
HGVS:
  • NC_000012.12:g.57500406G>A
  • NG_034077.1:g.17454G>A
  • NM_004990.4:c.1177G>AMANE SELECT
  • NP_004981.2:p.Ala393Thr
  • NC_000012.11:g.57894189G>A
  • NM_004990.3:c.1177G>A
  • P56192:p.Ala393Thr
Protein change:
A393T
Links:
UniProtKB: P56192#VAR_075362; OMIM: 156560.0007; dbSNP: rs141340466
NCBI 1000 Genomes Browser:
rs141340466
Molecular consequence:
  • NM_004990.4:c.1177G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002754940Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Likely benign
(Jul 7, 2020)
germlineclinical testing

Citation Link,

SCV004804445Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Jan 11, 2024)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in MARS identified in a specific type of pulmonary alveolar proteinosis alter methionyl-tRNA synthetase activity.

Comisso M, Hadchouel A, de Blic J, Mirande M.

FEBS J. 2018 Jul;285(14):2654-2661. doi: 10.1111/febs.14510. Epub 2018 May 25.

PubMed [citation]
PMID:
29775242

Biallelic Mutations of Methionyl-tRNA Synthetase Cause a Specific Type of Pulmonary Alveolar Proteinosis Prevalent on RĂ©union Island.

Hadchouel A, Wieland T, Griese M, Baruffini E, Lorenz-Depiereux B, Enaud L, Graf E, Dubus JC, Halioui-Louhaichi S, Coulomb A, Delacourt C, Eckstein G, Zarbock R, Schwarzmayr T, Cartault F, Meitinger T, Lodi T, de Blic J, Strom TM.

Am J Hum Genet. 2015 May 7;96(5):826-31. doi: 10.1016/j.ajhg.2015.03.010. Epub 2015 Apr 23.

PubMed [citation]
PMID:
25913036
PMCID:
PMC4570277
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002754940.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004804445.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: MARS1 c.1177G>A (p.Ala393Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282896 control chromosomes (gnomAD). c.1177G>A has been reported in the literature in individuals affected with pulmonary alveolar proteinosis or Charcot-Marie-Tooth disease without strong evidence of causality (Hadchouel_2015, La Fay_2021, Nam_2022). These reports do not provide unequivocal conclusions about association of the variant with MARS1-Related Disorders. Publications report experimental evidence evaluating an impact on protein function (Hadchouel_2015, Comiso_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 25913036, 29775242, 34496286, 34813128). ClinVar contains an entry for this variant (Variation ID: 242615). Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2024