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NM_000454.5(SOD1):c.34G>T (p.Asp12Tyr) AND Amyotrophic lateral sclerosis type 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 29, 2024
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:
RCV003486397.2

Allele description [Variation Report for NM_000454.5(SOD1):c.34G>T (p.Asp12Tyr)]

NM_000454.5(SOD1):c.34G>T (p.Asp12Tyr)

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.34G>T (p.Asp12Tyr)
HGVS:
  • NC_000021.9:g.31659803G>T
  • NG_008689.1:g.5182G>T
  • NG_200950.1:g.8G>T
  • NM_000454.5:c.34G>TMANE SELECT
  • NP_000445.1:p.Asp12Tyr
  • NP_000445.1:p.Asp12Tyr
  • LRG_652t1:c.34G>T
  • LRG_652:g.5182G>T
  • LRG_652p1:p.Asp12Tyr
  • NC_000021.8:g.33032116G>T
  • NM_000454.4:c.34G>T
  • NR_187558.1:n.222C>A
Protein change:
D12Y
Molecular consequence:
  • NM_000454.5:c.34G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_187558.1:n.222C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004239103Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 29, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital, SCV004239103.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
11not providednot providedclinical testing PubMed (1)

Description

Copy number variation analysis did not detect deletion in trans.

Description

This variant was detected in homozygous state in a male patient with a clinical diagnosis of ALS1 in his early 40s. Patient presented with rapidly progressive limb weakness over 1.5 years. The c.34G>T variant (p.(Asp12Tyr), also known as D11Y) has been reported in multiple heterozygous individuals with ALS1 in Italian population (PMID: 20740631, 21839474, 32987860, 35328090). It was suggested this variant has a founder effect in Italian population with specific phenotype and incomplete penetrance as a dominant trait (PMID: 22292847, 38112783). Described patients with heterozygous SOD1 c.34G>T variant showed slow progression with distal limb involvement, and predominant lower motor neuron signs (PMID: 32250500). It is found in control population at low frequency (rs762628133, gnomAD 0.0003%). In silico analysis suggests this variant to be damaging (REVEL: 0.65). The variant is in the critical superoxide dismutase copper/zinc binding domain (IPR001424). The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM2_supporting, PM3_supporting, PP1_moderate, PP3).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 23, 2024