ClinVar Genomic variation as it relates to human health
NM_015506.3(MMACHC):c.347T>C (p.Leu116Pro)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_015506.3(MMACHC):c.347T>C (p.Leu116Pro)
Variation ID: 1422 Accession: VCV000001422.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45508282 (GRCh38) [ NCBI UCSC ] 1: 45973954 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 15, 2018 Feb 14, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015506.3:c.347T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056321.2:p.Leu116Pro missense NM_001330540.2:c.176T>C NP_001317469.1:p.Leu59Pro missense NC_000001.11:g.45508282T>C NC_000001.10:g.45973954T>C NG_013378.1:g.13099T>C Q9Y4U1:p.Leu116Pro - Protein change
- L116P, L59P
- Other names
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- Canonical SPDI
- NC_000001.11:45508281:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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MMACHC | - | - |
GRCh38 GRCh37 |
521 | 612 |
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
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000001487.15 | |
not provided (1) |
no classification provided
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- | RCV002512644.1 |
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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Likely pathogenic
(Feb 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000789773.1
First in ClinVar: Jan 15, 2018 Last updated: Jan 15, 2018 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001162900.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Likely pathogenic
(Jul 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002811453.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004178158.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
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Pathogenic
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cobalamin C disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002247290.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the MMACHC protein (p.Leu116Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 116 of the MMACHC protein (p.Leu116Pro). This variant is present in population databases (rs121918240, gnomAD 0.04%). This missense change has been observed in individual(s) with homocystinuria, cblC type (PMID: 14568819, 16311595, 18245139, 20631720, 20924684; Invitae). ClinVar contains an entry for this variant (Variation ID: 1422). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MMACHC protein function. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 23, 2020)
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no assertion criteria provided
Method: research
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Methylmalonic acidemia with homocystinuria
Affected status: yes
Allele origin:
germline
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Neurology Department, Peking University First Hospital
Accession: SCV001423146.1
First in ClinVar: Jul 19, 2020 Last updated: Jul 19, 2020 |
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Pathogenic
(Jan 01, 2006)
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no assertion criteria provided
Method: literature only
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METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblC TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021642.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
In 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was made after the age of 20 years, Lerner-Ellis … (more)
In 2 patients in whom the diagnosis of methylmalonic aciduria and homocystinuria cblC type (MAHCC; 277400) was made after the age of 20 years, Lerner-Ellis et al. (2006) found compound heterozygosity in the MMACHC gene for the most common mutation, 271dupA (609831.0001), which in homozygous state causes early-onset disease, and a 347T-C transition, which was predicted to result in a leu116-to-pro (L116P) substitution. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Disorders of Intracellular Cobalamin Metabolism
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV003354476.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Disorders of Intracellular Cobalamin Metabolism. | Adam MP | - | 2021 | PMID: 20301503 |
Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function. | Froese DS | Biochemistry | 2012 | PMID: 22642810 |
Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. | Wang F | Journal of inherited metabolic disease | 2010 | PMID: 20924684 |
Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. | Liu MY | Journal of human genetics | 2010 | PMID: 20631720 |
Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. | Lerner-Ellis JP | Human mutation | 2009 | PMID: 19370762 |
The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. | Thauvin-Robinet C | Journal of neurology, neurosurgery, and psychiatry | 2008 | PMID: 18245139 |
Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. | Lerner-Ellis JP | Nature genetics | 2006 | PMID: 16311595 |
Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. | Roze E | Archives of neurology | 2003 | PMID: 14568819 |
Text-mined citations for rs121918240 ...
HelpRecord last updated Feb 20, 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.