ClinVar Genomic variation as it relates to human health
NM_000530.8(MPZ):c.106A>T (p.Arg36Trp)
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_000530.8(MPZ):c.106A>T (p.Arg36Trp)
Variation ID: 221065 Accession: VCV000221065.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.3 1: 161307386 (GRCh38) [ NCBI UCSC ] 1: 161277176 (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 19, 2017 Feb 20, 2024 Jan 27, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000530.8:c.106A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000521.2:p.Arg36Trp missense NM_001315491.2:c.106A>T NP_001302420.1:p.Arg36Trp missense NC_000001.11:g.161307386T>A NC_000001.10:g.161277176T>A NG_008055.1:g.7587A>T LRG_256:g.7587A>T LRG_256t1:c.106A>T - Protein change
- R36W
- Other names
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- Canonical SPDI
- NC_000001.11:161307385:T:A
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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MPZ | - | - |
GRCh38 GRCh37 |
640 | 675 |
Conditions - Germline
Condition
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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
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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 (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV000204639.9 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 14, 2023 | RCV000517562.11 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV000789432.1 |
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
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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
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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
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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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Pathogenic
(Oct 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520061.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment:
PS3, PS4, PM2, PM1, PP1
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Pathogenic
(May 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV000614098.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant occurs as the most likely explanation for disease in a significant number of internal cases, suggesting this variant is associated with disease. The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001782254.2
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
Reported previously in patient with acute onset painful polyneuropathy; his mother had milder symptoms and also harbored the variant (Burns et al., 2006); Published functional … (more)
Reported previously in patient with acute onset painful polyneuropathy; his mother had milder symptoms and also harbored the variant (Burns et al., 2006); Published functional studies demonstrate that R36W alters the normal MPZ function (Bai et al., 2018); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); 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: 16616845, 26310628, 22704856, 29687021, 23279346, 18636082, 14711881, 31278453, 16616847, 20461396, 33179255, 33359733, 33386210) (less)
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Pathogenic
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease, type I
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000262192.10
First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 36 of the MPZ protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 36 of the MPZ protein (p.Arg36Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of MPZ-related conditions (PMID: 16616847, 26310628). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221065). 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 not expected to disrupt MPZ protein function with a negative predictive value of 80%. This variant disrupts the p.Arg36 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14711881, 23279346). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium
Accession: SCV000928787.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
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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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Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype. | Callegari I | Journal of neurology | 2019 | PMID: 31278453 |
Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B. | Bai Y | Annals of clinical and translational neurology | 2018 | PMID: 29687021 |
Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. | Sanmaneechai O | Brain : a journal of neurology | 2015 | PMID: 26310628 |
Pupil abnormalities in 131 cases of genetically defined inherited peripheral neuropathy. | Houlden H | Eye (London, England) | 2009 | PMID: 18636082 |
Novel myelin protein zero mutation (Arg36Trp) in a patient with acute onset painful neuropathy. | Burns TM | Neuromuscular disorders : NMD | 2006 | PMID: 16616847 |
Genetic heterogeneity within a consanguineous family involving the LGMD 2D and the LGMD 2C genes. | Fendri K | Neuromuscular disorders : NMD | 2006 | PMID: 16616845 |
Phenotypic clustering in MPZ mutations. | Shy ME | Brain : a journal of neurology | 2004 | PMID: 14711881 |
Text-mined citations for rs864622732 ...
HelpRecord last updated May 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.