ClinVar Genomic variation as it relates to human health
NM_000530.8(MPZ):c.116A>C (p.His39Pro)
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.116A>C (p.His39Pro)
Variation ID: 217232 Accession: VCV000217232.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.3 1: 161307376 (GRCh38) [ NCBI UCSC ] 1: 161277166 (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 Oct 19, 2015 Feb 28, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000530.8:c.116A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000521.2:p.His39Pro missense NM_001315491.2:c.116A>C NP_001302420.1:p.His39Pro missense NC_000001.11:g.161307376T>G NC_000001.10:g.161277166T>G NG_008055.1:g.7597A>C LRG_256:g.7597A>C LRG_256t1:c.116A>C P25189:p.His39Pro - Protein change
- H39P
- Other names
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- Canonical SPDI
- NC_000001.11:161307375:T: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
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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
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
637 | 672 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 11, 2024 | RCV000206430.11 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Feb 21, 2023 | RCV000236108.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2020 | RCV002327052.1 |
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
(Aug 01, 2018)
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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: SCV000292950.9
First in ClinVar: Jul 25, 2016 Last updated: Apr 17, 2019 |
Comment:
The H39P pathogenic variant in the MPZ gene has been reported previously (using alternative nomenclature of H10P) in multiple unrelated individuals with late-onset neuropathy (CMT1B) … (more)
The H39P pathogenic variant in the MPZ gene has been reported previously (using alternative nomenclature of H10P) in multiple unrelated individuals with late-onset neuropathy (CMT1B) (Shy et al., 2004; Souayah et al., 2007). It was also identified in a family of 10 individuals with hereditary motor and sensory neuropathy, and absent in 200 control individuals (Kilfoyle et al., 2006). Functional studies suggest that H39P may result in partial loss of function (Grandis et al., 2008). The H39P variant was not observed in large population cohorts (Lek et al, 2016). Additionally, many other missense variants in nearby residues have also been reported in the Human Gene Mutation Database in association with MPZ-related neuropathies (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, H39P is interpreted to be a pathogenic variant and its presence is consistent with the diagnosis of an MPZ-related disorder in this individual. (less)
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Pathogenic
(Oct 21, 2020)
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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: SCV001713096.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Number of individuals with the variant: 1
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Pathogenic
(Sep 11, 2020)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002626957.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.H39P pathogenic mutation (also known as c.116A>C), located in coding exon 2 of the MPZ gene, results from an A to C substitution at … (more)
The p.H39P pathogenic mutation (also known as c.116A>C), located in coding exon 2 of the MPZ gene, results from an A to C substitution at nucleotide position 116. The histidine at codon 39 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple individuals with adult-onset demyelinating Charcot-Marie-Tooth disease type 1B and cosegregates with disease in two families (Shy ME et al. Brain, 2004 Feb;127:371-84; Kilfoyle DH et al. J. Neurol. Neurosurg. Psychiatry, 2006 Aug;77:963-6; Souayah N et al. J. Neurol. Sci., 2007 Dec;263:177-9). In addition to the clinical data presented in the literature, this alteration was found to be functionally abnormal in an assay of MPZ-mediated intercellular adhesion (Grandis M et al. Hum. Mol. Genet., 2008 Jul;17:1877-89). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 24, 2022)
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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 Inc
Accession: SCV000614099.7
First in ClinVar: Jul 25, 2016 Last updated: Jan 26, 2024 |
Comment:
This variant associates in multiple families with clinical features of Charcot-Marie Tooth disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). … (more)
This variant associates in multiple families with clinical features of Charcot-Marie Tooth disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. (less)
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Pathogenic
(Feb 21, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001160435.2
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The MPZ c.116A>C; p.His39Pro variant (rs371856018) is reported in the literature in numerous individuals affected with Charcot-Marie-Tooth syndrome or neuropathy (Kilfoyle 2006, Sanmaneechai 2015, Shy … (more)
The MPZ c.116A>C; p.His39Pro variant (rs371856018) is reported in the literature in numerous individuals affected with Charcot-Marie-Tooth syndrome or neuropathy (Kilfoyle 2006, Sanmaneechai 2015, Shy 2004, Souayah 2007). This variant was observed to co-segregate with disease in multiple families (Kilfoyle 2006, Shy 2004, Souayah 2007), including one large family where it was observed in 10 affected individuals and was absent from 24 unaffected individuals (Kilfoyle 2006). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, including its occurrence in a large number of affected individuals, this variant is considered to be pathogenic. References: Kilfoyle DH et al. Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Aug;77(8):963-6. Sanmaneechai O et al. Genotype-phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene. Brain. 2015 Nov;138(Pt 11):3180-92. Shy ME et al. Phenotypic clustering in MPZ mutations. Brain. 2004 Feb;127(Pt 2):371-84. Souayah N et al. Rare myelin protein zero sequence variant in late onset CMT1B. J Neurol Sci. 2007 Dec 15;263(1-2):177-9. (less)
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Pathogenic
(Jan 11, 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: SCV000261054.11
First in ClinVar: Feb 02, 2016 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 39 of the MPZ protein (p.His39Pro). … (more)
This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 39 of the MPZ protein (p.His39Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 14711881, 16844954, 17602703, 26310628). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His10Pro. ClinVar contains an entry for this variant (Variation ID: 217232). 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 MPZ protein function. Experimental studies have shown that this missense change affects MPZ function (PMID: 18337304). For these reasons, this variant has been classified as Pathogenic. (less)
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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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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 |
Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties. | Saporta MA | Experimental neurology | 2015 | PMID: 25448007 |
Different cellular and molecular mechanisms for early and late-onset myelin protein zero mutations. | Grandis M | Human molecular genetics | 2008 | PMID: 18337304 |
Rare myelin protein zero sequence variant in late onset CMT1B. | Souayah N | Journal of the neurological sciences | 2007 | PMID: 17602703 |
Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis. | Kilfoyle DH | Journal of neurology, neurosurgery, and psychiatry | 2006 | PMID: 16844954 |
Phenotypic clustering in MPZ mutations. | Shy ME | Brain : a journal of neurology | 2004 | PMID: 14711881 |
Text-mined citations for rs371856018 ...
HelpRecord last updated Apr 15, 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.