NM_003680.4(YARS1):c.946G>A (p.Ala316Thr) AND Charcot-Marie-Tooth disease, dominant intermediate C

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Jan 23, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000276182.4

Allele description [Variation Report for NM_003680.4(YARS1):c.946G>A (p.Ala316Thr)]

NM_003680.4(YARS1):c.946G>A (p.Ala316Thr)

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.946G>A (p.Ala316Thr)
HGVS:
  • NC_000001.11:g.32782500C>T
  • NG_008408.1:g.40533G>A
  • NM_003680.3:c.946G>A
  • NM_003680.4:c.946G>AMANE SELECT
  • NP_003671.1:p.Ala316Thr
  • NP_003671.1:p.Ala316Thr
  • LRG_273t1:c.946G>A
  • LRG_273:g.40533G>A
  • LRG_273p1:p.Ala316Thr
  • NC_000001.10:g.33248101C>T
Protein change:
A316T
Links:
dbSNP: rs138454151
NCBI 1000 Genomes Browser:
rs138454151
Molecular consequence:
  • NM_003680.3:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003680.4:c.946G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000357240Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Likely benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV001382411Invitaecriteria provided, single submitter
Uncertain significance
(Jan 23, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

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):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000357240.3

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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

From Invitae, SCV001382411.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces alanine with threonine at codon 316 of the YARS protein (p.Ala316Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs138454151, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with YARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 297154). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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

Last Updated: Nov 27, 2021

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