Variant summary: The MMACHC c.615C>G (p.Tyr205X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.666C>A (p.Tyr222X) has been classified as pathogenic by our laboratory. This variant was found in 5/246214 control chromosomes (gnomAD) at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant of interst has been reported in multiple affected compound heterozygote and homozygote cblC pts (Lerner-Ellis_2006). In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_015506.3(MMACHC):c.615C>G (p.Tyr205Ter)
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_015506.3(MMACHC):c.615C>G (p.Tyr205Ter)
Variation ID: 281007 Accession: VCV000281007.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 45508981 (GRCh38) [ NCBI UCSC ] 1: 45974653 (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 Dec 6, 2016 Jun 17, 2024 Mar 16, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015506.3:c.615C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056321.2:p.Tyr205Ter nonsense NM_001330540.2:c.444C>G NP_001317469.1:p.Tyr148Ter nonsense NC_000001.11:g.45508981C>G NC_000001.10:g.45974653C>G NG_013378.1:g.13798C>G - Protein change
- Y205*, Y148*
- Other names
- -
- Canonical SPDI
- NC_000001.11:45508980:C:G
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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
Help
The frequency of the allele represented by this VCV record.
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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. |
|||
| LOC129930446 | - | - | - | GRCh38 | - | 67 |
| MMACHC | - | - |
GRCh38 GRCh37 |
527 | 619 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 16, 2024 | RCV000267790.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001275217.1 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 7, 2020 | RCV000723444.8 |
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
(May 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331039.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Apr 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790733.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
|
|
|
Pathogenic
(Nov 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic acidemia with homocystinuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919668.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The MMACHC c.615C>G (p.Tyr205X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense … (more)
Variant summary: The MMACHC c.615C>G (p.Tyr205X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.666C>A (p.Tyr222X) has been classified as pathogenic by our laboratory. This variant was found in 5/246214 control chromosomes (gnomAD) at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant of interst has been reported in multiple affected compound heterozygote and homozygote cblC pts (Lerner-Ellis_2006). In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Oct 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001802367.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33587123, 19760748, 16311595, 20631720, 25388550, 30863077) (less)
|
|
|
Pathogenic
(Feb 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002817318.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified homozygous and compound heterozygous in multiple individuals … (more)
This variant is expected to result in the loss of a functional protein. This variant has been identified homozygous and compound heterozygous in multiple individuals with clinical features associated with this gene (PMID: 16311595, 19370762, 19760748, 23746552). The frequency of this variant in the general population is consistent with pathogenicity for a recessive disorder (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
|
|
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Pathogenic
(Apr 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cobalamin C disease
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV004178211.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
|
|
|
Pathogenic
(Nov 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cobalamin C disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001227233.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr205*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Tyr205*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs747527726, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with cobalamin C deficiency (PMID: 16311595, 19914430, 20631720, 25388550). ClinVar contains an entry for this variant (Variation ID: 281007). 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
(Mar 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cobalamin C disease
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001522713.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria with homocystinuria cblC type
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001460141.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
Comment:
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33587123, 19760748, 16311595, 20631720, 25388550, 30863077)
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified homozygous and compound heterozygous in multiple individuals with clinical features associated with this gene (PMID: 16311595, 19370762, 19760748, 23746552). The frequency of this variant in the general population is consistent with pathogenicity for a recessive disorder (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr205*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs747527726, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with cobalamin C deficiency (PMID: 16311595, 19914430, 20631720, 25388550). ClinVar contains an entry for this variant (Variation ID: 281007). 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.
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: The MMACHC c.615C>G (p.Tyr205X) variant results in a premature termination codon, predicted to cause a truncated or absent MMACHC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.666C>A (p.Tyr222X) has been classified as pathogenic by our laboratory. This variant was found in 5/246214 control chromosomes (gnomAD) at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic MMACHC variant (0.0030542). The variant of interst has been reported in multiple affected compound heterozygote and homozygote cblC pts (Lerner-Ellis_2006). In addition, a clinical diagnostic laboratory classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 78 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33587123, 19760748, 16311595, 20631720, 25388550, 30863077)
Comment:
This variant is expected to result in the loss of a functional protein. This variant has been identified homozygous and compound heterozygous in multiple individuals with clinical features associated with this gene (PMID: 16311595, 19370762, 19760748, 23746552). The frequency of this variant in the general population is consistent with pathogenicity for a recessive disorder (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Comment:
This sequence change creates a premature translational stop signal (p.Tyr205*) in the MMACHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 78 amino acid(s) of the MMACHC protein. This variant is present in population databases (rs747527726, gnomAD 0.009%). This premature translational stop signal has been observed in individuals with cobalamin C deficiency (PMID: 16311595, 19914430, 20631720, 25388550). ClinVar contains an entry for this variant (Variation ID: 281007). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Co-occurrence of the Poland sequence in a patient with the cobalamin C defect: more than just a coincidence? | Weisfeld-Adams JD | Journal of inherited metabolic disease | 2015 | PMID: 25388550 |
| Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. | Liu MY | Journal of human genetics | 2010 | PMID: 20631720 |
| Asymptomatic maternal combined homocystinuria and methylmalonic aciduria (cblC) detected through low carnitine levels on newborn screening. | Lin HJ | The Journal of pediatrics | 2009 | PMID: 19914430 |
| Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. | Lerner-Ellis JP | Nature genetics | 2006 | PMID: 16311595 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MMACHC | - | - | - | - |
Text-mined citations for rs747527726 ...
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 Sep 29, 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.