NM_012208.4(HARS2):c.956T>C (p.Ile319Thr) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 3, 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:: RCV000725134.15

Allele description [Variation Report for NM_012208.4(HARS2):c.956T>C (p.Ile319Thr)]

NM_012208.4(HARS2):c.956T>C (p.Ile319Thr)

Gene:

HARS2:histidyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_012208.4(HARS2):c.956T>C (p.Ile319Thr)

Other names:

p.I319T:ATC>ACC

HGVS:

NC_000005.10:g.140697165T>C
NG_021415.1:g.10733T>C
NM_001278731.2:c.881T>C
NM_001278732.2:c.524T>C
NM_001363535.2:c.974T>C
NM_001363536.2:c.746T>C
NM_012208.4:c.956T>CMANE SELECT
NP_001265660.1:p.Ile294Thr
NP_001265661.1:p.Ile175Thr
NP_001350464.1:p.Ile325Thr
NP_001350465.1:p.Ile249Thr
NP_036340.1:p.Ile319Thr
LRG_1376t1:c.956T>C
LRG_1376:g.10733T>C
LRG_1376p1:p.Ile319Thr
NC_000005.9:g.140076750T>C
NM_012208.2:c.956T>C

Protein change:

I175T

Links:

dbSNP: rs74755920

NCBI 1000 Genomes Browser:

rs74755920

Molecular consequence:

NM_001278731.2:c.881T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001278732.2:c.524T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363535.2:c.974T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001363536.2:c.746T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_012208.4:c.956T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000251610	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 3, 2024)	germline	clinical testing	Citation Link,
SCV000334355	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Sep 14, 2015)	germline	clinical testing	Citation Link,
SCV004319424	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 11, 2024)	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

SCV000251610

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 3, 2024)

germline

clinical testing

Citation Link,

SCV000334355

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Sep 14, 2015)

germline

clinical testing

Citation Link,

SCV004319424

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 11, 2024)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	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 GeneDx, SCV000251610.18

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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

From Eurofins Ntd Llc (ga), SCV000334355.4

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004319424.1

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 319 of the HARS2 protein (p.Ile319Thr). This variant is present in population databases (rs74755920, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with HARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214545). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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: Sep 29, 2024

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