NM_004990.4(MARS1):c.1392G>T (p.Trp464Cys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 13, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003033977.3

Allele description [Variation Report for NM_004990.4(MARS1):c.1392G>T (p.Trp464Cys)]

NM_004990.4(MARS1):c.1392G>T (p.Trp464Cys)

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.1392G>T (p.Trp464Cys)

HGVS:

NC_000012.12:g.57511721G>T
NG_034077.1:g.28769G>T
NM_004990.4:c.1392G>TMANE SELECT
NP_004981.2:p.Trp464Cys
NC_000012.11:g.57905504G>T

Protein change:

W464C

Molecular consequence:

NM_004990.4:c.1392G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Severe early-onset pulmonary alveolar proteinosis due to MARS deficiency
Synonyms:: PULMONARY ALVEOLAR PROTEINOSIS, REUNION ISLAND; Interstitial lung and liver disease
Identifiers:: MONDO: MONDO:0014206; MedGen: C4225400; OMIM: 615486

Name:: Charcot-Marie-Tooth disease axonal type 2U
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2U; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2U
Identifiers:: MONDO: MONDO:0014566; MedGen: C4084821; Orphanet: 397735; OMIM: 616280

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CRAT37 [Homo sapiens]
CRAT37 [Homo sapiens]
Gene ID:101926928

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CRAT37 AND (alive[prop]) (1)
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RPS17 AND (alive[prop]) (1984)
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APRT AND (alive[prop]) (920)
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MYH15 myosin heavy chain 15 [Homo sapiens]
MYH15 myosin heavy chain 15 [Homo sapiens]
Gene ID:22989

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003323896	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003323896

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003323896.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with MARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 464 of the MARS protein (p.Trp464Cys).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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