Variant summary: MUT c.2150G>T (p.Gly717Val) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain and C-terminal of the Methylmalonyl-CoA mutase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 277004 control chromosomes (gnomAD). The variant, c.2150G>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as a homozygous and compound heterozygous allele (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Worgan_2006). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified 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_000255.4(MMUT):c.2150G>T (p.Gly717Val)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000255.4(MMUT):c.2150G>T (p.Gly717Val)
Variation ID: 1881 Accession: VCV000001881.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 6p12.3 6: 49431831 (GRCh38) [ NCBI UCSC ] 6: 49399544 (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 Mar 24, 2015 Feb 20, 2024 Jan 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000255.4:c.2150G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000246.2:p.Gly717Val missense NC_000006.12:g.49431831C>A NC_000006.11:g.49399544C>A NG_007100.1:g.36309G>T P22033:p.Gly717Val NP_000246.1:p.Gly717Val - Protein change
- G717V
- Other names
- -
- Canonical SPDI
- NC_000006.12:49431830:C:A
-
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), exomes 0.00005
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00026
- 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. |
|||
| MMUT | - | - |
GRCh38 GRCh37 |
1080 | 1093 | |
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 (1) |
no assertion criteria provided
|
Jan 1, 2006 | RCV000001958.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000078445.24 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2018 | RCV000781613.9 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Sep 28, 2023 | RCV000174456.25 | |
|
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001276629.9 |
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
(May 25, 2018)
|
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: SCV000919785.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: MUT c.2150G>T (p.Gly717Val) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain and C-terminal of the Methylmalonyl-CoA mutase … (more)
Variant summary: MUT c.2150G>T (p.Gly717Val) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain and C-terminal of the Methylmalonyl-CoA mutase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 277004 control chromosomes (gnomAD). The variant, c.2150G>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as a homozygous and compound heterozygous allele (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Worgan_2006). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 10, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225762.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 30, 2019 |
Number of individuals with the variant: 7
Sex: mixed
|
|
|
Pathogenic
(Sep 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017616.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Apr 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788461.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
|
|
|
Pathogenic
(Jun 14, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000583146.3
First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015 |
Comment:
Published functional studies demonstrate this variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992); The majority of missense variants in this gene … (more)
Published functional studies demonstrate this variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9285782, 25125334, 24077912, 25087612, 1346616, 16281286, 26790480, 31622506, 27535533) (less)
|
|
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Pathogenic
(Apr 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893719.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000963062.7
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 717 of the MUT protein (p.Gly717Val). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 717 of the MUT protein (p.Gly717Val). This variant is present in population databases (rs121918252, gnomAD 0.07%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 1346616, 16281286, 27233228). ClinVar contains an entry for this variant (Variation ID: 1881). 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) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 1346616, 25125334). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463081.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Jan 01, 2006)
|
no assertion criteria provided
Method: literature only
|
METHYLMALONIC ACIDURIA, mut(-) TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022116.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 25, 2021 |
Comment on evidence:
In a patient with a mut(-) MMA (251000) phenotype previously characterized by Ledley et al. (1990), Crane et al. (1992) identified 3 novel base changes … (more)
In a patient with a mut(-) MMA (251000) phenotype previously characterized by Ledley et al. (1990), Crane et al. (1992) identified 3 novel base changes in the MUT gene. They concluded that the particular phenotype was due to a homozygous gly717-to-val (G717V) substitution, which resulted in an unstable enzyme. This mutation showed interallelic complementation with the R93H mutation (609058.0004). The patient was also homozygous also 2 other mutations which were presumably neutral: his532-to-arg (H532R) and val671-to-ile (V671I). Crane et al. (1992) compared the phenotype in the original patient and in 2 others with the G717V mutation. All 3 presented in the first years of life with multiple episodes of life-threatening organic acidosis and hyperammonemia. None had evidence of disease in the perinatal period, and all 3 were of low-normal intelligence. The authors concluded that the phenotype was intermediate between the fulminant and benign forms of methylmalonic aciduria, and suggested that the level of residual MUT enzyme activity associated with the G717V mutation may be close to the threshold required in vivo for maintaining metabolic homeostasis. In a mutation screen of 160 patients with mut MMA, Worgan et al. (2006) found the G717V mutation in 12 of 29 black patients. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000258513.2
First in ClinVar: Jun 28, 2015 Last updated: Oct 01, 2022
Comment:
mut¯ enzymatic subtype
|
|
Comment:
Comment:
Published functional studies demonstrate this variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9285782, 25125334, 24077912, 25087612, 1346616, 16281286, 26790480, 31622506, 27535533)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 717 of the MUT protein (p.Gly717Val). This variant is present in population databases (rs121918252, gnomAD 0.07%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 1346616, 16281286, 27233228). ClinVar contains an entry for this variant (Variation ID: 1881). 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) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 1346616, 25125334). 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: MUT c.2150G>T (p.Gly717Val) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain and C-terminal of the Methylmalonyl-CoA mutase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 277004 control chromosomes (gnomAD). The variant, c.2150G>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as a homozygous and compound heterozygous allele (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Worgan_2006). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate this variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9285782, 25125334, 24077912, 25087612, 1346616, 16281286, 26790480, 31622506, 27535533)
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 717 of the MUT protein (p.Gly717Val). This variant is present in population databases (rs121918252, gnomAD 0.07%). This missense change has been observed in individual(s) with methylmalonic acidemia (PMID: 1346616, 16281286, 27233228). ClinVar contains an entry for this variant (Variation ID: 1881). 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) performed at Invitae indicates that this missense variant is expected to disrupt MUT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MUT function (PMID: 1346616, 25125334). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Isolated Methylmalonic Acidemia. | Adam MP | - | 2022 | PMID: 20301409 |
| Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations. | Chu J | Molecular genetics and metabolism | 2016 | PMID: 27233228 |
| Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia. | Harrington EA | Human gene therapy | 2016 | PMID: 26790480 |
| Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency. | Forny P | Human mutation | 2014 | PMID: 25125334 |
| Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. | Worgan LC | Human mutation | 2006 | PMID: 16281286 |
| Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation. | Janata J | Human molecular genetics | 1997 | PMID: 9285782 |
| Homology modeling of human methylmalonyl-CoA mutase: a structural basis for point mutations causing methylmalonic aciduria. | Thomä NH | Protein science : a publication of the Protein Society | 1996 | PMID: 8880917 |
| Phenotype of disease in three patients with identical mutations in methylmalonyl CoA mutase. | Crane AM | Human genetics | 1992 | PMID: 1351030 |
| Cloning and expression of a mutant methylmalonyl coenzyme A mutase with altered cobalamin affinity that causes mut- methylmalonic aciduria. | Crane AM | The Journal of clinical investigation | 1992 | PMID: 1346616 |
| Mutation eliminating mitochondrial leader sequence of methylmalonyl-CoA mutase causes muto methylmalonic acidemia. | Ledley FD | Proceedings of the National Academy of Sciences of the United States of America | 1990 | PMID: 1970180 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUT | - | - | - | - |
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Text-mined citations for rs121918252 ...
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 Nov 03, 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.