NM_005861.4(STUB1):c.427AAG[2] (p.Lys145del) AND Spinocerebellar ataxia 48

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 15, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002221280.3

Allele description [Variation Report for NM_005861.4(STUB1):c.427AAG[2] (p.Lys145del)]

NM_005861.4(STUB1):c.427AAG[2] (p.Lys145del)

Gene:

STUB1:STIP1 homology and U-box containing protein 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_005861.4(STUB1):c.427AAG[2] (p.Lys145del)

HGVS:

NC_000016.10:g.681506AAG[2]
NG_034141.1:g.6396AAG[2]
NM_001293197.2:c.211AAG[2]
NM_005861.4:c.427AAG[2]MANE SELECT
NM_005861.4:c.433_435del
NP_001280126.1:p.Lys73del
NP_005852.2:p.Lys145del
NC_000016.9:g.731505_731507del
NC_000016.9:g.731506AAG[2]
NM_005861.2:c.433_435del
NM_005861.4:c.433_435delMANE SELECT
NM_005861.4:c.433_435delAAGMANE SELECT

Protein change:

K145del

Links:

dbSNP: rs779647632

NCBI 1000 Genomes Browser:

rs779647632

Molecular consequence:

NM_001293197.2:c.211AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_005861.4:c.427AAG[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002498665	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 32713943, 34663476, 34906452, 25741868
SCV004032314	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002498665

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 5, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004032314

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 15, 2023)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment.

Roux T, Barbier M, Papin M, Davoine CS, Sayah S, Coarelli G, Charles P, Marelli C, Parodi L, Tranchant C, Goizet C, Klebe S, Lohmann E, Van Maldergem L, van Broeckhoven C, Coutelier M, Tesson C, Stevanin G, Duyckaerts C, Brice A, Durr A; SPATAX network..

Genet Med. 2020 Nov;22(11):1851-1862. doi: 10.1038/s41436-020-0899-x. Epub 2020 Jul 27. Erratum in: Genet Med. 2021 Oct;23(10):2021. doi: 10.1038/s41436-020-01064-y.

PubMed [citation]

PMID:: 32713943

Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias.

Cheng HL, Shao YR, Dong Y, Dong HL, Yang L, Ma Y, Shen Y, Wu ZY.

Transl Neurodegener. 2021 Oct 18;10(1):40. doi: 10.1186/s40035-021-00264-z.

PubMed [citation]

PMID:: 34663476
PMCID:: PMC8522248

See all PubMed Citations (4)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002498665.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region of the STUB1 protein, p.(Lys145del). The region deleted is highly conserved (100 vertebrates, UCSC), and is located in the coiled-coil domain. This variant is present in a single individual in the European (non-Finnish) population from the population database gnomAD v2.1 (1/112,126 alleles). This variant has been reported in at least five probands with a phenotype consistent with spinocerebellar ataxia 48 (SCA48; PMID: 32713943, 34906452; Shariant; Royal Melbourne Hospital). The variant has been reported to segregate with SCA48 in three affected family members from a single family (PMID: 34906452). This variant has been observed in trans with the variant c.433A>C, p.(Lys145Gln) (PMID: 34663476) which is classified as pathogenic/likely pathogenic (ClinVar ID: 212325) in an individual with spinocerebellar ataxia autosomal recessive 16 (SCAR16). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3, PS4_Supporting, PM2_Supporting, PM4_Supporting, PP1.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004032314.1

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

Description

Criteria applied: PS4_MOD,PM3,PM2_SUP,PM4_SUP

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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