NM_003680.4(YARS1):c.176T>C (p.Ile59Thr) AND Charcot-Marie-Tooth disease dominant intermediate C

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 2, 2024
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:: RCV000698802.11

Allele description [Variation Report for NM_003680.4(YARS1):c.176T>C (p.Ile59Thr)]

NM_003680.4(YARS1):c.176T>C (p.Ile59Thr)

Gene:

YARS1:tyrosyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p35.1

Genomic location:

Preferred name:

NM_003680.4(YARS1):c.176T>C (p.Ile59Thr)

HGVS:

NC_000001.11:g.32810939A>G
NG_008408.1:g.12094T>C
NM_003680.4:c.176T>CMANE SELECT
NP_003671.1:p.Ile59Thr
NP_003671.1:p.Ile59Thr
LRG_273t1:c.176T>C
LRG_273:g.12094T>C
LRG_273p1:p.Ile59Thr
NC_000001.10:g.33276540A>G
NM_003680.3:c.176T>C

Protein change:

I59T

Links:

dbSNP: rs774466323

NCBI 1000 Genomes Browser:

rs774466323

Molecular consequence:

NM_003680.4:c.176T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on protein abundance [Variation Ontology: 0052]

Condition(s)

Name:: Charcot-Marie-Tooth disease dominant intermediate C (CMTDIC)
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, DOMINANT INTERMEDIATE C
Identifiers:: MONDO: MONDO:0012012; MedGen: C1842237; OMIM: 608323

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000827488	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 2, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34352414, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000827488

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 2, 2024)

germline

clinical testing

PubMed (2)
[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

Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease.

Estève C, Roman C, DeLeusse C, Baravalle M, Bertaux K, Blanc F, Bourgeois P, Bresson V, Cano A, Coste ME, Delteil C, Lacoste C, Loosveld M, De Paula AM, Monnier AS, Secq V, Levy N, Badens C, Fabre A.

Eur J Med Genet. 2021 Oct;64(10):104294. doi: 10.1016/j.ejmg.2021.104294. Epub 2021 Aug 3.

PubMed [citation]

PMID:: 34352414

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, SCV000827488.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 59 of the YARS protein (p.Ile59Thr). This variant is present in population databases (rs774466323, gnomAD 0.004%). This missense change has been observed in individual(s) with YARS-related multi-systemic syndrome (PMID: 34352414). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 576327). 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 YARS protein function with a positive predictive value of 80%. Studies have shown that this missense change alters YARS gene expression (PMID: 34352414). 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.

#	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: May 16, 2025

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