NM_002109.6(HARS1):c.679T>G (p.Ser227Ala) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 19, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV001000572.9

Allele description [Variation Report for NM_002109.6(HARS1):c.679T>G (p.Ser227Ala)]

NM_002109.6(HARS1):c.679T>G (p.Ser227Ala)

Gene:

HARS1:histidyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_002109.6(HARS1):c.679T>G (p.Ser227Ala)

HGVS:

NC_000005.10:g.140677705A>C
NG_032158.1:g.18682T>G
NM_001258040.3:c.559T>G
NM_001258041.3:c.619T>G
NM_001258042.3:c.499T>G
NM_001289092.2:c.457T>G
NM_001289093.2:c.337T>G
NM_001289094.2:c.592T>G
NM_002109.6:c.679T>GMANE SELECT
NP_001244969.1:p.Ser187Ala
NP_001244970.1:p.Ser207Ala
NP_001244971.1:p.Ser167Ala
NP_001276021.1:p.Ser153Ala
NP_001276022.1:p.Ser113Ala
NP_001276023.1:p.Ser198Ala
NP_002100.2:p.Ser227Ala
LRG_1374t1:c.679T>G
LRG_1374:g.18682T>G
LRG_1374p1:p.Ser227Ala
NC_000005.9:g.140057290A>C
NM_002109.3:c.679T>G
NM_002109.5:c.679T>G

Protein change:

S113A

Links:

dbSNP: rs768076848

NCBI 1000 Genomes Browser:

rs768076848

Molecular consequence:

NM_001258040.3:c.559T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258041.3:c.619T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258042.3:c.499T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001289092.2:c.457T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001289093.2:c.337T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001289094.2:c.592T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002109.6:c.679T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001157536	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jun 17, 2019)	germline	clinical testing	Citation Link,
SCV002755232	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Oct 19, 2020)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001157536

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Jun 17, 2019)

germline

clinical testing

Citation Link,

SCV002755232

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Oct 19, 2020)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157536.1

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

Description

The HARS c.679T>G; p.Ser227Ala variant has been reported once in a CMT patient who carried a second variant of the same gene (Lupo 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.09 percent in the Latino population (identified on 31 out of 35,428 chromosomes) and has been reported to the ClinVar database (ClinVar ID: 576600). The serine at position 227 is weakly conserved and computational analyses of the effects of the p.Ser227Ala variant on protein structure and function is conflicting (SIFT: damaging, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Ser227Ala variant with certainty.

#	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 Ambry Genetics, SCV002755232.2

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 26, 2024

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