NM_004990.4(MARS1):c.2104C>T (p.Arg702Trp) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 6, 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:: RCV002228219.11

Allele description [Variation Report for NM_004990.4(MARS1):c.2104C>T (p.Arg702Trp)]

NM_004990.4(MARS1):c.2104C>T (p.Arg702Trp)

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.2104C>T (p.Arg702Trp)

HGVS:

NC_000012.12:g.57514958C>T
NG_027674.1:g.10560G>A
NG_034077.1:g.32006C>T
NM_004990.4:c.2104C>TMANE SELECT
NP_004981.2:p.Arg702Trp
NC_000012.11:g.57908741C>T
NM_004990.3:c.2104C>T

Protein change:

R702W; ARG702TRP

Links:

OMIM: 156560.0004; dbSNP: rs587777228

NCBI 1000 Genomes Browser:

rs587777228

Molecular consequence:

NM_004990.4:c.2104C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002509769	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 6, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24482476, 28708278, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002509769

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 6, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GMH, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, El Din Mahmoud IG, Bouslam N, et al.

Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.

PubMed [citation]

PMID:: 24482476
PMCID:: PMC4157572

Whole-exome sequencing is a valuable diagnostic tool for inherited peripheral neuropathies: Outcomes from a cohort of 50 families.

Hartley T, Wagner JD, Warman-Chardon J, Tétreault M, Brady L, Baker S, Tarnopolsky M, Bourque PR, Parboosingh JS, Smith C, McInnes B, Innes AM, Bernier F, Curry CJ, Yoon G, Horvath GA, Bareke E, Gillespie M; FORGE Canada Consortium.; Care4Rare Canada Consortium., Majewski J, Bulman DE, et al.

Clin Genet. 2018 Feb;93(2):301-309. doi: 10.1111/cge.13101. Epub 2017 Dec 12.

PubMed [citation]

PMID:: 28708278

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002509769.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 120187). This missense change has been observed in individual(s) with clinical features of hereditary spastic paraplegia or hereditary sensory neuropathy (PMID: 24482476, 28708278). This variant is present in population databases (rs587777228, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 702 of the MARS protein (p.Arg702Trp).

#	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: Nov 3, 2024

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