ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- no assertion criteria provided
- Submissions:
- 1
- First in ClinVar:
- Apr 1, 2019
- Most recent Submission:
- Feb 2, 2015
- Last evaluated:
- Dec 1, 2014
- Accession:
- VCV000018391.1
- Variation ID:
- 18391
- Description:
- single nucleotide variant
Help
NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)
- Allele ID
- 33430
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 10p11.23
- Genomic location
- 10: 30313926 (GRCh38) GRCh38 UCSC
- 10: 30602855 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_018109.4:c.1432A>G MANE Select NP_060579.3:p.Asn478Asp missense NC_000010.11:g.30313926T>C NC_000010.10:g.30602855T>C NG_028096.1:g.40413A>G Q9NVV4:p.Asn478Asp - Protein change
- N478D
- Other names
- -
- Canonical SPDI
- NC_000010.11:30313925:T:C
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- The Genome Aggregation Database (gnomAD) 0.00001
- Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
- ClinGen: CA113782
- UniProtKB: Q9NVV4#VAR_064907
- OMIM: 613669.0001
- dbSNP: rs267606900
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 1 | no assertion criteria provided | Dec 1, 2014 | RCV000000002.3 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Dec 01, 2014)
|
no assertion criteria provided
Method: literature only
|
SPASTIC ATAXIA 4, AUTOSOMAL RECESSIVE (1 family)
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020145.2
First in ClinVar: Apr 04, 2013 Last updated: Feb 02, 2015 |
Comment on evidence:
In 6 affected members of a large consanguineous family of Old Order Amish origin with spastic ataxia-4 (SPAX4; 613672), Crosby et al. (2010) identified a … (more)
In 6 affected members of a large consanguineous family of Old Order Amish origin with spastic ataxia-4 (SPAX4; 613672), Crosby et al. (2010) identified a homozygous 1432A-G transition in exon 9 of the MTPAP gene, resulting in an asn478-to-asp (N478D) substitution in a highly conserved region in an N-P-F-E sequence. The phenotype was characterized by early childhood onset of progressive cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy. The mutation was not found in 600 control chromosomes from individuals of European ancestry and was found in 1 of 200 control chromosomes from the same Ohio Amish community. Assays assessing mitochondrial poly(A) tails of the mitochondrial-encoded transcripts RNA14 and MTCO1 (516030) indicated that homozygous carriers of the MTPAP mutation had significantly increased percentages of oligoadenylated (less than 10 nucleotides) compared to polyadenylated (greater than 30 nucleotides) transcripts compared to unaffected parents who were heterozygous for the N478D mutation. Although the exact function of polyadenylation of mitochondrial mRNA transcripts remained unclear, the process is essential for maintaining proper mRNA expression in mitochondria, and disruption of this process leads to mitochondrial dysfunction, as shown by the neurodegeneration in this family. Wilson et al. (2014) performed studies on fibroblasts from 2 patients and 1 unaffected obligate mutation carrier from the Amish family with SPAX4 reported by Crosby et al. (2010). Mitochondrial mRNA from patient cells showed a lack of polyadenylation and a concomitant increase in oligoadenylated species. Heterozygous cells were similar to controls, with a mild increase in oligoadenylated mRNA. Homozygous mutant cell lines showed a decrease in oxidative phosphorylation activity, as well as a severe decrease in the amounts and activities of mitochondrial complexes I and IV. The effects on the steady-state levels and translation of mRNA species in patient cells varied depending on the transcript. The findings were consistent with a selective defect in mitochondrial gene expression, and these defects could be rescued by expression of wildtype MTPAP. The mutant protein showed normal localization, but was unable to extend unadenylated MTND3 (516002) substrate in vitro, consistent with a loss of enzyme function. The addition of LRPPRC (607544)/SLIRP (610211), a mitochondrial RNA-binding complex, mildly enhanced adenylation activity of the mutant protein. Wilson et al. (2014) concluded that alterations in poly(A) length can dysregulate posttranscriptional expression and cause a pathogenic lack of respiratory chain complexes. (less)
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression. | Wilson WC | Human molecular genetics | 2014 | PMID: 25008111 |
| Defective mitochondrial mRNA maturation is associated with spastic ataxia. | Crosby AH | American journal of human genetics | 2010 | PMID: 20970105 |
Text-mined citations for rs267606900...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Apr 24, 2022