Variant summary: MMAA c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246142 control chromosomes (gnomAD). c.586C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (Plessl_2017, Sun_2015, Lubrano_2013, Nizon_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_172250.3(MMAA):c.586C>T (p.Arg196Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_172250.3(MMAA):c.586C>T (p.Arg196Ter)
Variation ID: 466217 Accession: VCV000466217.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q31.21 4: 145646009 (GRCh38) [ NCBI UCSC ] 4: 146567161 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 26, 2017 Jun 17, 2024 Mar 17, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_172250.3:c.586C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_758454.1:p.Arg196Ter nonsense NC_000004.12:g.145646009C>T NC_000004.11:g.146567161C>T NG_007536.2:g.51968C>T LRG_1301:g.51968C>T LRG_1301t1:c.586C>T LRG_1301p1:p.Arg196Ter - Protein change
- R196*
- Other names
- -
- Canonical SPDI
- NC_000004.12:145646008:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MMAA | - | - |
GRCh38 GRCh37 |
550 | 586 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000545383.17 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 8, 2019 | RCV001193915.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2023 | RCV001584283.5 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363089.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: MMAA c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MMAA c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246142 control chromosomes (gnomAD). c.586C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (Plessl_2017, Sun_2015, Lubrano_2013, Nizon_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Centre for Inherited Metabolic Diseases, Karolinska University Hospital
Accession: SCV001554461.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Family history: no
Secondary finding: no
|
|
|
Pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001813964.2
First in ClinVar: Sep 08, 2021 Last updated: Sep 07, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27629047, 29996803, 34670123, 25567501, 23711287, 25636100, 16247646, 31622506, 33726816, 32754920, 33453710, 21545677) (less)
|
|
|
Pathogenic
(Aug 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000641767.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 466217). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 466217). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 21545677, 23711287, 25636100; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg196*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192). (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805029.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(Dec 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193093.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 01, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793859.2
First in ClinVar: Dec 26, 2017 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Feb 05, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001190759.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria cblA type
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452010.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27629047, 29996803, 34670123, 25567501, 23711287, 25636100, 16247646, 31622506, 33726816, 32754920, 33453710, 21545677)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 466217). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 21545677, 23711287, 25636100; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg196*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192).
Germline Functional Evidence
| 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. |
Comment:
Variant summary: MMAA c.586C>T (p.Arg196X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.1e-06 in 246142 control chromosomes (gnomAD). c.586C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (Plessl_2017, Sun_2015, Lubrano_2013, Nizon_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication evaluated patient derived fibroblasts and demonstrated severely decreased enzyme activity values in homozygotes (Plessl 2017). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27629047, 29996803, 34670123, 25567501, 23711287, 25636100, 16247646, 31622506, 33726816, 32754920, 33453710, 21545677)
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 466217). This premature translational stop signal has been observed in individuals with methylmalonic acidemia (PMID: 21545677, 23711287, 25636100; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg196*) in the MMAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MMAA are known to be pathogenic (PMID: 15523652, 15781192).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria. | Plessl T | Human mutation | 2017 | PMID: 28497574 |
| [Detection of pathogenic mutations for methylmalonic acidemia using new-generation semiconductor targeted sequencing]. | Sun Y | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2015 | PMID: 25636100 |
| Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. | Nizon M | Orphanet journal of rare diseases | 2013 | PMID: 24059531 |
| Pregnancy in a methylmalonic acidemia patient with kidney transplantation: a case report. | Lubrano R | American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons | 2013 | PMID: 23711287 |
| Methylmalonic acidemia mimicking diabetic ketoacidosis in an infant. | Guven A | Pediatric diabetes | 2012 | PMID: 21545677 |
| Renal transplantation in a 14-year-old girl with vitamin B12-responsive cblA-type methylmalonic acidaemia. | Coman D | Pediatric nephrology (Berlin, Germany) | 2006 | PMID: 16247646 |
| Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants. | Martínez MA | Molecular genetics and metabolism | 2005 | PMID: 15781192 |
| Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism. | Lerner-Ellis JP | Human mutation | 2004 | PMID: 15523652 |
Text-mined citations for rs1029096863 ...
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 Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.