NM_000454.5(SOD1):c.26T>A (p.Leu9Gln) AND Amyotrophic lateral sclerosis type 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 30, 2022
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:: RCV003050563.3

Allele description [Variation Report for NM_000454.5(SOD1):c.26T>A (p.Leu9Gln)]

NM_000454.5(SOD1):c.26T>A (p.Leu9Gln)

Genes:

SOD1-DT:SOD1 divergent transcript [Gene - HGNC]
SOD1:superoxide dismutase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.11

Genomic location:

Preferred name:

NM_000454.5(SOD1):c.26T>A (p.Leu9Gln)

HGVS:

NC_000021.9:g.31659795T>A
NG_008689.1:g.5174T>A
NM_000454.5:c.26T>AMANE SELECT
NP_000445.1:p.Leu9Gln
NP_000445.1:p.Leu9Gln
LRG_652t1:c.26T>A
LRG_652:g.5174T>A
LRG_652p1:p.Leu9Gln
NC_000021.8:g.33032108T>A
NM_000454.4:c.26T>A

Protein change:

L9Q

Molecular consequence:

NM_000454.5:c.26T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Amyotrophic lateral sclerosis type 1 (ALS1)
Synonyms:: AMYOTROPHIC LATERAL SCLEROSIS 1, FAMILIAL
Identifiers:: MONDO: MONDO:0007103; MedGen: C1862939; Orphanet: 803; OMIM: 105400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003443389	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 30, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19091752, 23280792, 9131652, 22292843, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443389

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 30, 2022)

germline

clinical testing

PubMed (5)
[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

Expression of amyotrophic lateral sclerosis-linked SOD1 mutant increases the neurotoxic potential of microglia via TLR2.

Liu Y, Hao W, Dawson A, Liu S, Fassbender K.

J Biol Chem. 2009 Feb 6;284(6):3691-9. doi: 10.1074/jbc.M804446200. Epub 2008 Dec 17.

PubMed [citation]

PMID:: 19091752

A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.

Fujisawa T, Homma K, Yamaguchi N, Kadowaki H, Tsuburaya N, Naguro I, Matsuzawa A, Takeda K, Takahashi Y, Goto J, Tsuji S, Nishitoh H, Ichijo H.

Ann Neurol. 2012 Nov;72(5):739-49. doi: 10.1002/ana.23668.

PubMed [citation]

PMID:: 23280792

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443389.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

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. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19091752, 23280792). 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 SOD1 protein function. This variant is also known as p.Leu8Gln. This missense change has been observed in individual(s) with clinical features of amyotrophic lateral sclerosis (PMID: 9131652, 22292843). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 9 of the SOD1 protein (p.Leu9Gln).

#	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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