NM_000454.5(SOD1):c.255G>C (p.Leu85Phe) AND Amyotrophic lateral sclerosis type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 13, 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:: RCV001061075.8

Allele description [Variation Report for NM_000454.5(SOD1):c.255G>C (p.Leu85Phe)]

NM_000454.5(SOD1):c.255G>C (p.Leu85Phe)

Gene:

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.255G>C (p.Leu85Phe)

HGVS:

NC_000021.9:g.31667273G>C
NG_008689.1:g.12652G>C
NM_000454.5:c.255G>CMANE SELECT
NP_000445.1:p.Leu85Phe
LRG_652t1:c.255G>C
LRG_652:g.12652G>C
NC_000021.8:g.33039586G>C
NM_000454.4:c.255G>C

Protein change:

L85F

Links:

dbSNP: rs1315541036

NCBI 1000 Genomes Browser:

rs1315541036

Molecular consequence:

NM_000454.5:c.255G>C - 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
SCV001225806	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 13, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9506558, 20577002, 21329474, 22670878, 24325798, 25792239, 23280792, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001225806

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 13, 2022)

germline

clinical testing

PubMed (8)
[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

Mutations in all five exons of SOD-1 may cause ALS.

Shaw CE, Enayat ZE, Chioza BA, Al-Chalabi A, Radunovic A, Powell JF, Leigh PN.

Ann Neurol. 1998 Mar;43(3):390-4.

PubMed [citation]

PMID:: 9506558

SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations.

Millecamps S, Salachas F, Cazeneuve C, Gordon P, Bricka B, Camuzat A, Guillot-Noël L, Russaouen O, Bruneteau G, Pradat PF, Le Forestier N, Vandenberghe N, Danel-Brunaud V, Guy N, Thauvin-Robinet C, Lacomblez L, Couratier P, Hannequin D, Seilhean D, Le Ber I, Corcia P, Camu W, et al.

J Med Genet. 2010 Aug;47(8):554-60. doi: 10.1136/jmg.2010.077180. Epub 2010 Jun 24.

PubMed [citation]

PMID:: 20577002

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001225806.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 85 of the SOD1 protein (p.Leu85Phe). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 9506558, 20577002, 21329474, 22670878, 24325798, 25792239). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Leu84Phe. ClinVar contains an entry for this variant (Variation ID: 855744). 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. Experimental studies have shown that this missense change affects SOD1 function (PMID: 23280792). For these reasons, this variant has been classified as Pathogenic.

#	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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