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NM_005861.4(STUB1):c.746G>T (p.Gly249Val) AND Spinocerebellar ataxia 48

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 2, 2021
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:
RCV002225177.2

Allele description [Variation Report for NM_005861.4(STUB1):c.746G>T (p.Gly249Val)]

NM_005861.4(STUB1):c.746G>T (p.Gly249Val)

Genes:
STUB1:STIP1 homology and U-box containing protein 1 [Gene - OMIM - HGNC]
JMJD8:jumonji domain containing 8 [Gene - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p13.3
Genomic location:
Preferred name:
NM_005861.4(STUB1):c.746G>T (p.Gly249Val)
HGVS:
  • NC_000016.10:g.682241G>T
  • NG_034141.1:g.7131G>T
  • NG_132623.1:g.565G>T
  • NM_001005920.4:c.*553C>AMANE SELECT
  • NM_001293197.2:c.530G>T
  • NM_001323918.3:c.*587C>A
  • NM_001323919.3:c.*553C>A
  • NM_001323920.3:c.*553C>A
  • NM_001323922.3:c.*587C>A
  • NM_005861.4:c.746G>TMANE SELECT
  • NP_001280126.1:p.Gly177Val
  • NP_005852.2:p.Gly249Val
  • NC_000016.9:g.732241G>T
  • NR_136650.3:n.1446C>A
  • NR_136651.3:n.1451C>A
  • NR_136652.3:n.1361C>A
Protein change:
G177V
Links:
dbSNP: rs2151506587
NCBI 1000 Genomes Browser:
rs2151506587
Molecular consequence:
  • NM_001005920.4:c.*553C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001323918.3:c.*587C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001323919.3:c.*553C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001323920.3:c.*553C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001323922.3:c.*587C>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001293197.2:c.530G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005861.4:c.746G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_136650.3:n.1446C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_136651.3:n.1451C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_136652.3:n.1361C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Spinocerebellar ataxia 48
Identifiers:
MONDO: MONDO:0032526; MedGen: C4748158; OMIM: 618093

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002503708Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jul 2, 2021) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Pakdaman Y, Berland S, Bustad HJ, Erdal S, Thompson BA, James PA, Power KN, Ellingsen S, Krooni M, Berge LI, Sexton A, Bindoff LA, Knappskog PM, Johansson S, Aukrust I.

Int J Mol Sci. 2021 May 30;22(11). doi:pii: 5870. 10.3390/ijms22115870.

PubMed [citation]
PMID:
34070858
PMCID:
PMC8199271

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 Molecular Genetics, Royal Melbourne Hospital, SCV002503708.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change is predicted to replace glycine with valine at codon 249 of the STUB1 protein (p.(Gly249Val)). The glycine residue is evolutionarily conserved (100 vertebrates, UCSC), and located in the ubiquitin ligase (U-box) domain (UniProt). There is a large physicochemical difference between glycine and valine. The variant is absent in a large population cohort (gnomAD v2.1). In vitro functional assays demonstrated that the variant impaired ubiquitination activity on the Hsc70 substrate and inability to perform self-ubiquitination (PMID: 34070858). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Supporting, PM2_Supporting, PP3.

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

Last Updated: Sep 1, 2024