U.S. flag

An official website of the United States government

NM_006796.3(AFG3L2):c.1875G>A (p.Met625Ile) AND Spastic ataxia 5

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Aug 3, 2022
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV000149914.8

Allele description [Variation Report for NM_006796.3(AFG3L2):c.1875G>A (p.Met625Ile)]

NM_006796.3(AFG3L2):c.1875G>A (p.Met625Ile)

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.1875G>A (p.Met625Ile)
Other names:
p.Met625Ile
HGVS:
  • NC_000018.10:g.12340306C>T
  • NG_023361.1:g.41971G>A
  • NM_006796.3:c.1875G>AMANE SELECT
  • NP_006787.2:p.Met625Ile
  • NP_006787.2:p.Met625Ile
  • LRG_666t1:c.1875G>A
  • LRG_666:g.41971G>A
  • LRG_666p1:p.Met625Ile
  • NC_000018.9:g.12340305C>T
  • NM_006796.2:c.1875G>A
Protein change:
M625I; MET625ILE
Links:
OMIM: 604581.0011; dbSNP: rs727502823
NCBI 1000 Genomes Browser:
rs727502823
Molecular consequence:
  • NM_006796.3:c.1875G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Spastic ataxia 5
Synonyms:
Spastic ataxia 5, autosomal recessive
Identifiers:
MONDO: MONDO:0013776; MedGen: C3280977; Orphanet: 313772; OMIM: 614487

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000196765OMIM
no assertion criteria provided
Pathogenic
(Jan 1, 2015)
germlineliterature only

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

SCV002818548Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN
no assertion criteria provided
Uncertain significance
(Aug 3, 2022)
paternalclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedpaternalyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, Joensuu T, Canafoglia L, Franceschetti S, Michelucci R, Markkinen S, Heron SE, Hildebrand MS, Andermann E, Andermann F, Gambardella A, Tinuper P, Licchetta L, Scheffer IE, Criscuolo C, Filla A, Ferlazzo E, et al.

Nat Genet. 2015 Jan;47(1):39-46. doi: 10.1038/ng.3144. Epub 2014 Nov 17.

PubMed [citation]
PMID:
25401298
PMCID:
PMC4281260

Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.

Franchino CA, Brughera M, Baderna V, De Ritis D, Rocco A, Seneca S, Regal L, Podini P, D'Antonio M, Toro C, Quattrini A, Scalais E, Maltecca F.

Brain. 2024 Mar 1;147(3):1043-1056. doi: 10.1093/brain/awad340.

PubMed [citation]
PMID:
37804316
PMCID:
PMC10907083

Details of each submission

From OMIM, SCV000196765.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In 2 unrelated Italian patients with a variant of autosomal recessive spastic ataxia-5 (SPAX5; 614487), presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous c.1875G-A transition in the AFG3L2 gene, resulting in a met625-to-ile (M625I) substitution at a conserved residue in the proteolytic domain. The mutation, which was found by exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant were not performed. Haplotype analysis suggested that the mutation was identical by descent, although the patients were not known to be related. The patients were ascertained from a larger cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing.

In a girl (patient 2) with SPAX5, Franchino et al. (2024) identified compound heterozygous mutations in the AFG3L2 gene: M625I and a 1-bp duplication (c.245dup; 604581.0020) predicted to result in a frameshift and premature termination (Asn82LysfsTer6). The mutations were identified by sequencing of a panel of nuclear genes associated with mitochondrial disease. Each parent was a carrier of one of the mutations. Fibroblasts from the patient demonstrated reduced protein expression of AFG3L2, reduced TMRM fluorescence, and decreased mitochondrial membrane potential.

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

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV002818548.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providedBloodnot provided1not providednot providednot provided

Last Updated: Jul 23, 2024