This sequence change creates a premature translational stop signal (p.Gln95*) 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). This variant is present in population databases (rs104893846, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15523652). ClinVar contains an entry for this variant (Variation ID: 3158). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_172250.3(MMAA):c.283C>T (p.Gln95Ter)
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.
(7)
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
7
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.283C>T (p.Gln95Ter)
Variation ID: 3158 Accession: VCV000003158.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 4q31.21 4: 145639422 (GRCh38) [ NCBI UCSC ] 4: 146560574 (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 Apr 4, 2013 Feb 14, 2024 Nov 3, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_172250.3:c.283C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_758454.1:p.Gln95Ter nonsense NC_000004.12:g.145639422C>T NC_000004.11:g.146560574C>T NG_007536.2:g.45381C>T LRG_1301:g.45381C>T LRG_1301t1:c.283C>T LRG_1301p1:p.Gln95Ter - Protein change
- Q95*
- Other names
- -
- Canonical SPDI
- NC_000004.12:145639421: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
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00017
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 3, 2023 | RCV000003308.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 10, 2023 | RCV003155012.8 |
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
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001419137.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln95*) in the MMAA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln95*) 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). This variant is present in population databases (rs104893846, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15523652). ClinVar contains an entry for this variant (Variation ID: 3158). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000793358.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
|
|
|
Pathogenic
(Feb 10, 2023)
|
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: SCV003844517.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: MMAA c.283C>T (p.Gln95X) 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.283C>T (p.Gln95X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9.2e-05 in 251242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (9.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.283C>T has been reported in the literature as a homozygous and compound heterozygous state in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017, Dobson_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblA type
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193119.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Nov 26, 2002)
|
no assertion criteria provided
Method: literature only
|
METHYLMALONIC ACIDURIA, cblA TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000023466.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 14, 2021 |
Comment on evidence:
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified heterozygosity for a C-to-T … (more)
In a fibroblast cell line from a patient with methylmalonic aciduria of the cblA type (251100), Dobson et al. (2002) identified heterozygosity for a C-to-T transition at nucleotide 283 of the MMAA gene, resulting in a gln95-to-ter (Q95X) substitution. (less)
|
|
|
Pathogenic
(May 04, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria cblA type
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002084820.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Methylmalonic aciduria, cblA type
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000258472.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
Variant summary: MMAA c.283C>T (p.Gln95X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9.2e-05 in 251242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (9.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.283C>T has been reported in the literature as a homozygous and compound heterozygous state in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017, Dobson_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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:
This sequence change creates a premature translational stop signal (p.Gln95*) 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). This variant is present in population databases (rs104893846, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with methylmalonic aciduria due to cobalamin A deficiency (PMID: 15523652). ClinVar contains an entry for this variant (Variation ID: 3158). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: MMAA c.283C>T (p.Gln95X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 9.2e-05 in 251242 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MMAA causing Methylmalonic Acidemia (9.2e-05 vs 0.0025), allowing no conclusion about variant significance. c.283C>T has been reported in the literature as a homozygous and compound heterozygous state in multiple individuals affected with Methylmalonic Acidemia (Lerner-Ellis_2004, Plessl_2017, Dobson_2002). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Isolated Methylmalonic Acidemia. | Adam MP | - | 2022 | PMID: 20301409 |
| Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. | Stranneheim H | Genome medicine | 2021 | PMID: 33726816 |
| Protein destabilization and loss of protein-protein interaction are fundamental mechanisms in cblA-type methylmalonic aciduria. | Plessl T | Human mutation | 2017 | PMID: 28497574 |
| 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 |
| Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. | Dobson CM | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 12438653 |
Text-mined citations for rs104893846 ...
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 Dec 28, 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.