NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys) AND Spinocerebellar ataxia type 28

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 1, 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:: RCV000005804.6

Allele description [Variation Report for NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys)]

NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys)

Gene:

AFG3L2:AFG3 like matrix AAA peptidase subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18p11.21

Genomic location:

Preferred name:

NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys)

HGVS:

NC_000018.10:g.12337445C>T
NG_023361.1:g.44832G>A
NM_006796.3:c.2071G>AMANE SELECT
NP_006787.2:p.Glu691Lys
NP_006787.2:p.Glu691Lys
LRG_666t1:c.2071G>A
LRG_666:g.44832G>A
LRG_666p1:p.Glu691Lys
NC_000018.9:g.12337444C>T
NM_006796.2:c.2071G>A
Q9Y4W6:p.Glu691Lys

Protein change:

E691K; GLU691LYS

Links:

UniProtKB: Q9Y4W6#VAR_063545; OMIM: 604581.0001; dbSNP: rs151344520

NCBI 1000 Genomes Browser:

rs151344520

Molecular consequence:

NM_006796.3:c.2071G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Spinocerebellar ataxia type 28 (SCA28)
Identifiers:: MONDO: MONDO:0012450; MedGen: C1853249; Orphanet: 101109; OMIM: 610246

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025986	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 16251216, 20208537
SCV002572855	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20208537, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000025986

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 2010)

germline

literature only

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

SCV002572855

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (2)
[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	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2.

Cagnoli C, Mariotti C, Taroni F, Seri M, Brussino A, Michielotto C, Grisoli M, Di Bella D, Migone N, Gellera C, Di Donato S, Brusco A.

Brain. 2006 Jan;129(Pt 1):235-42. Epub 2005 Oct 26.

PubMed [citation]

PMID:: 16251216

Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.

Di Bella D, Lazzaro F, Brusco A, Plumari M, Battaglia G, Pastore A, Finardi A, Cagnoli C, Tempia F, Frontali M, Veneziano L, Sacco T, Boda E, Brussino A, Bonn F, Castellotti B, Baratta S, Mariotti C, Gellera C, Fracasso V, Magri S, Langer T, et al.

Nat Genet. 2010 Apr;42(4):313-21. doi: 10.1038/ng.544. Epub 2010 Mar 7.

PubMed [citation]

PMID:: 20208537

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000025986.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 11 affected members of an Italian family with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), reported by Cagnoli et al. (2006), Di Bella et al. (2010) identified a heterozygous 2071G-A transition in exon 16 of the AFG3L2 gene, resulting in a glu691-to-lys (E691K) substitution within the highly conserved proteolytic domain. One asymptomatic individual carried the mutation, which was not found in 400 controls. Molecular modeling showed that the E691K substitution affects a residue that sits in the middle of the central pore surrounding the exit from the proteolytic chamber on the matrix side of the complex. In vitro studies in yeast showed that the mutant protein was expressed but unable to restore an endogenous respiration defect. Coexpression with wildtype AFG3L2 or paraplegin (602783) did not restore respiration, consistent with a dominant-negative effect. Further studies showed that the mutant protein had impaired proteolytic activity.

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

From 3billion, SCV002572855.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20208537). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.20). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with AFG3L2-related disorder (ClinVar ID: VCV000005470 / PMID: 20208537). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 20208537). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 24, 2022

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