NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg) AND Spinocerebellar ataxia type 28

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jul 18, 2017
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:: RCV000023378.8

Allele description [Variation Report for NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg)]

NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg)

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.2011G>A (p.Gly671Arg)

HGVS:

NC_000018.10:g.12337505C>T
NG_023361.1:g.44772G>A
NM_006796.3:c.2011G>AMANE SELECT
NP_006787.2:p.Gly671Arg
NP_006787.2:p.Gly671Arg
LRG_666t1:c.2011G>A
LRG_666:g.44772G>A
LRG_666p1:p.Gly671Arg
NC_000018.9:g.12337504C>T
NM_006796.2:c.2011G>A
Q9Y4W6:p.Gly671Arg
p.G671R

Protein change:

G671R; GLY671ARG

Links:

UniProtKB: Q9Y4W6#VAR_064407; OMIM: 604581.0008; dbSNP: rs151344517

NCBI 1000 Genomes Browser:

rs151344517

Molecular consequence:

NM_006796.3:c.2011G>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
SCV000044669	OMIM	no assertion criteria provided	Pathogenic (Oct 1, 2010)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000054613	GeneReviews	no classification provided	not provided	germline	literature only
SCV000746662	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20725928, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000044669

OMIM

no assertion criteria provided

Pathogenic
(Oct 1, 2010)

germline

literature only

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

SCV000054613

GeneReviews

no classification provided

not provided

germline

literature only

SCV000746662

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 18, 2017)

unknown

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	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
White	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias.

Cagnoli C, Stevanin G, Brussino A, Barberis M, Mancini C, Margolis RL, Holmes SE, Nobili M, Forlani S, Padovan S, Pappi P, Zaros C, Leber I, Ribai P, Pugliese L, Assalto C, Brice A, Migone N, Dürr A, Brusco A.

Hum Mutat. 2010 Oct;31(10):1117-24. doi: 10.1002/humu.21342.

PubMed [citation]

PMID:: 20725928

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 OMIM, SCV000044669.3

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

Description

In affected members of 2 unrelated families with autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246), Cagnoli et al. (2010) identified a heterozygous 2011G-A transition in exon 16 of the AFG3L2 gene, resulting in a gly671-to-arg (G671R) substitution in a highly conserved residue in the C-terminal proteolytic peptidase-M41 domain. Haplotype analysis indicated a founder effect. Gly671 is located on the surface of the AFG3L2 complex, and the mutation was predicted to decrease the electrostatic potential difference between the inner mitochondrial membrane side and the matrix side of the hexameric complex, as well as decrease the central pore dipole. These findings suggested a destabilizing effect. The mutation was not identified in 380 French or Italian control chromosomes.

#	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 GeneReviews, SCV000054613.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	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

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (2)

#	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	(GTR000553916.1)	1	not provided	not provided	not provided

Last Updated: Oct 1, 2022

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