NM_015340.4(LARS2):c.899C>T (p.Thr300Met) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003556221.3

Allele description [Variation Report for NM_015340.4(LARS2):c.899C>T (p.Thr300Met)]

NM_015340.4(LARS2):c.899C>T (p.Thr300Met)

Gene:

LARS2:leucyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_015340.4(LARS2):c.899C>T (p.Thr300Met)

HGVS:

NC_000003.12:g.45476508C>T
NG_033907.3:g.92945C>T
NM_001368263.1:c.899C>T
NM_015340.4:c.899C>TMANE SELECT
NP_001355192.1:p.Thr300Met
NP_056155.1:p.Thr300Met
LRG_1353t1:c.899C>T
LRG_1353:g.92945C>T
LRG_1353p1:p.Thr300Met
NC_000003.11:g.45518000C>T
NG_033907.1:g.92926C>T
NG_033907.2:g.92926C>T
NM_015340.3:c.899C>T

Protein change:

T300M; THR300MET

Links:

OMIM: 604544.0004; dbSNP: rs864309642

NCBI 1000 Genomes Browser:

rs864309642

Molecular consequence:

NM_001368263.1:c.899C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_015340.4:c.899C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004292687	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26657938, 28492532
SCV005081019	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 28, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292687

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 1, 2022)

germline

clinical testing

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

SCV005081019

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 28, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.

Soldà G, Caccia S, Robusto M, Chiereghin C, Castorina P, Ambrosetti U, Duga S, Asselta R.

J Hum Genet. 2016 Apr;61(4):295-300. doi: 10.1038/jhg.2015.149. Epub 2015 Dec 10.

PubMed [citation]

PMID:: 26657938
PMCID:: PMC4817218

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, SCV004292687.1

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

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. 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 not expected to disrupt LARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 203990). This missense change has been observed in individual(s) with Perrault syndrome (PMID: 26657938). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 300 of the LARS2 protein (p.Thr300Met).

#	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

From GeneDx, SCV005081019.1

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 32423379, 32767731, 26657938)

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

Last Updated: Sep 29, 2024

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