NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant disease (PMID: 12471062, 24516753, 30022420, 26589311). Functional assessments of this variant are not available in the literature. c.197-1G>T has been observed in population frequency databases (gnomAD: SAS 0.03%). In summary, NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
ClinVar Genomic variation as it relates to human health
NM_052845.4(MMAB):c.197-1G>T
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_052845.4(MMAB):c.197-1G>T
Variation ID: 219008 Accession: VCV000219008.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.11 12: 110006669 (GRCh37) [ NCBI UCSC ] 12: 109568864 (GRCh38) [ 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 Jan 16, 2016 Jun 17, 2024 Feb 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_052845.4:c.197-1G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000012.12:g.109568864C>A NC_000012.11:g.110006669C>A NG_007096.1:g.9634G>T NG_007702.1:g.170C>A LRG_156:g.170C>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000012.12:109568863:C:A
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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
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
- 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. |
|||
| MMAB | - | - |
GRCh38 GRCh37 |
462 | 557 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Feb 25, 2024 | RCV000203326.22 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 30, 2022 | RCV000590462.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Nov 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV002060277.2
First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022 |
Comment:
NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant … (more)
NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant disease (PMID: 12471062, 24516753, 30022420, 26589311). Functional assessments of this variant are not available in the literature. c.197-1G>T has been observed in population frequency databases (gnomAD: SAS 0.03%). In summary, NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Jul 08, 2016)
|
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: SCV000699779.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting … (more)
Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblB type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149836.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
|
|
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Pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848703.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic … (more)
The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic aciduria cobalamin B type (Lerner-Ellis 2006 PMID: 16410054, Dobson 2002 PMID: 12471062, Al-Shamsi 2014 PMID: 24516753, Shafaat 2018 PMID: 30022420, Al-Jasmi 2016 PMID: 26589311). It has also been reported in ClinVar (Variation ID 219008). It has also been identified in 1/67974 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MMAB gene is an established disease mechanism in autosomal recessive methylmalonic aciduria cobalamin B type. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic aciduria cobalamin B type. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_Strong. (less)
|
|
|
Pathogenic
(Feb 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004193146.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria, cblB type
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001400676.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). This variant is present in population databases (rs763935916, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria, cblB type
(Autosomal recessive inheritance)
Affected status: no
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000579473.1
First in ClinVar: Jan 16, 2016 Last updated: Jan 16, 2016 |
Comment:
The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster.
Indication for testing: Sibling of child suspected with Methylmalonic aciduria
Geographic origin: India
Method: DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. The sequences obtained were aligned to the human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
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Pathogenic
(Oct 19, 2020)
|
no assertion criteria provided
Method: research
|
Vitamin B12-responsive methylmalonic acidemia type cblB
Affected status: yes
Allele origin:
germline
|
Shieh Lab, University of California, San Francisco
Accession: SCV001441636.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria cblB type
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001459243.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jun 01, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
|
Baumgartner lab, University Children's Hospital Zurich
Accession: SCV001738791.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Methylmalonic aciduria, cblB type
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000258532.2
First in ClinVar: Jan 16, 2016 Last updated: Oct 01, 2022 |
|
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| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic.
Comment:
The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic aciduria cobalamin B type (Lerner-Ellis 2006 PMID: 16410054, Dobson 2002 PMID: 12471062, Al-Shamsi 2014 PMID: 24516753, Shafaat 2018 PMID: 30022420, Al-Jasmi 2016 PMID: 26589311). It has also been reported in ClinVar (Variation ID 219008). It has also been identified in 1/67974 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MMAB gene is an established disease mechanism in autosomal recessive methylmalonic aciduria cobalamin B type. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic aciduria cobalamin B type. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_Strong.
Comment:
This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). This variant is present in population databases (rs763935916, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster.
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:
NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant classified as pathogenic in the context of methylmalonic acidemia, cblB type. c.197-1G>T has been observed in cases with relevant disease (PMID: 12471062, 24516753, 30022420, 26589311). Functional assessments of this variant are not available in the literature. c.197-1G>T has been observed in population frequency databases (gnomAD: SAS 0.03%). In summary, NM_052845.3(MMAB):c.197-1G>T is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
Variant summary: The c.197-1G>T in MMAB gene is a splice-site variant that alters a highly conserved nucleotide with 5/5 in silico tools via Alamut predicting this variant to disrupt a canonical acceptor sequence. These predictions were confirmed by functional assay (Dobson, 2002). The variant is present in the large, broad control population, ExAC with an allele frequency of 3/121374 (1/40458), which does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene of 1/714 (0.0014). The variant was found in multiple affected individuals with an established diagnosis of methylmalonic aciduria. Fibroblast lines from homozygous carriers had decreased incorporation of label from [14C] propionate into cellular macromolecules and decreased synthesis of AdoCbl from exogenous [57Co]CNCb. Lastly, reputable databases/diagnostic centers classify the variant of interest as Pathogenic. Taken together, the variant has been classified as Pathogenic.
Comment:
The c.197-1G>T variant in MMAB (also known as IVS2-1G>T) has been reported, in the homozygous and compound heterozygous state, in several individuals affected with methylmalonic aciduria cobalamin B type (Lerner-Ellis 2006 PMID: 16410054, Dobson 2002 PMID: 12471062, Al-Shamsi 2014 PMID: 24516753, Shafaat 2018 PMID: 30022420, Al-Jasmi 2016 PMID: 26589311). It has also been reported in ClinVar (Variation ID 219008). It has also been identified in 1/67974 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the MMAB gene is an established disease mechanism in autosomal recessive methylmalonic aciduria cobalamin B type. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive methylmalonic aciduria cobalamin B type. ACMG/AMP Criteria applied: PM2_Supporting, PVS1_Strong, PM3_Strong.
Comment:
This sequence change affects an acceptor splice site in intron 2 of the MMAB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MMAB are known to be pathogenic (PMID: 15781192, 16410054). This variant is present in population databases (rs763935916, gnomAD 0.03%). Disruption of this splice site has been observed in individuals with methylmalonic aciduria cobalamin B type (PMID: 16410054, 30022420). This variant is also known as IVS2-1G>T. ClinVar contains an entry for this variant (Variation ID: 219008). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The observed variant is not reported in 1000 genomes database and is likely to be pathogenic by In Silico analysis using mutation taster.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Isolated Methylmalonic Acidemia. | Adam MP | - | 2022 | PMID: 20301409 |
| Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort. | Shafaat M | Metabolic brain disease | 2018 | PMID: 30022420 |
| Inborn Errors of Metabolism in the United Arab Emirates: Disorders Detected by Newborn Screening (2011-2014). | Al-Jasmi FA | JIMD reports | 2016 | PMID: 26589311 |
| Mutation Spectrum and Birth Prevalence of Inborn Errors of Metabolism among Emiratis: A study from Tawam Hospital Metabolic Center, United Arab Emirates. | Al-Shamsi A | Sultan Qaboos University medical journal | 2014 | PMID: 24516753 |
| Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. | Lerner-Ellis JP | Molecular genetics and metabolism | 2006 | PMID: 16410054 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| 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 cblB complementation group of vitamin B12-dependent methylmalonic aciduria. | Dobson CM | Human molecular genetics | 2002 | PMID: 12471062 |
Text-mined citations for rs763935916 ...
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.