ClinVar Genomic variation as it relates to human health
NM_005797.4(MPZL2):c.72del (p.Ile24fs)
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_005797.4(MPZL2):c.72del (p.Ile24fs)
Variation ID: 585268 Accession: VCV000585268.21
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 118263084 (GRCh38) [ NCBI UCSC ] 11: 118133799 (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 Feb 25, 2019 Mar 16, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005797.4:c.72del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005788.1:p.Ile24fs frameshift NM_144765.3:c.72del NP_658911.1:p.Ile24fs frameshift NC_000011.10:g.118263084del NC_000011.9:g.118133799del - Protein change
- I24fs
- Other names
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- Canonical SPDI
- NC_000011.10:118263083:T:
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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) 0.00068
The Genome Aggregation Database (gnomAD) 0.00069
The Genome Aggregation Database (gnomAD), exomes 0.00081
Exome Aggregation Consortium (ExAC) 0.00082
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00152
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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MPZL2 | - | - |
GRCh38 GRCh37 |
40 | 72 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2022 | RCV000710018.9 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000820138.13 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 21, 2023 | RCV003965455.1 |
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
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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
(Nov 30, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hearing loss, autosomal recessive 111
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Accession: SCV001526024.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple consanguineous families … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple consanguineous families with slowly progressive, moderate to severe hearing loss [PMID 29982980, 29961571] (less)
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Likely pathogenic
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing loss, autosomal recessive 111
Affected status: yes
Allele origin:
germline
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Neurogenetic Laboratory, Second Faculty of Medicine, Charles University
Accession: SCV001571597.1
First in ClinVar: Apr 22, 2021 Last updated: Apr 22, 2021 |
Clinical Features:
Hearing impairment (present)
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Pathogenic
(Jun 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hearing loss, autosomal recessive 111
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002555687.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: MPZL2 c.72delA (p.Ile24MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MPZL2 c.72delA (p.Ile24MetfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Hearing Loss in HGMD. The variant allele was found at a frequency of 0.00081 in 250850 control chromosomes (gnomAD). c.72delA has been reported in the literature in multiple homozygous individuals affected with Hearing Loss, Autosomal Recessive 111 and seggregated with the disease (example: Bademci_2018). These data indicate that the variant is very likely to be associated with disease. Six submitters provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hearing loss, autosomal recessive 111
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579296.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: male
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Pathogenic
(May 08, 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: SCV001825233.6
First in ClinVar: Sep 08, 2021 Last updated: May 20, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29961571, 29982980, 34426522, 34062854, 33234333, 33594163, 27535533, 35599849, 36147510) (less)
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Pathogenic
(Jan 18, 2024)
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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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Invitae
Accession: SCV000960835.3
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ile24Metfs*22) in the MPZL2 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Ile24Metfs*22) in the MPZL2 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MPZL2 cause disease. This variant is present in population databases (rs752672077, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with nonsyndromic hearing loss (PMID: 29961571, 29982980). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585268). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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MPZL2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004778128.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MPZL2 c.72delA variant is predicted to result in a frameshift and premature protein termination (p.Ile24Metfs*22). This variant has been reported in patients with autosomal … (more)
The MPZL2 c.72delA variant is predicted to result in a frameshift and premature protein termination (p.Ile24Metfs*22). This variant has been reported in patients with autosomal recessive hearing loss (Bademci. 2018. PubMed ID: 29982980; Wesdorp. 2018. PubMed ID: 29961571; Safka Brozkova. 2021. PubMed ID: 34062854). This variant is reported in 0.38% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-118133798-CT-C). Frameshift variants in MPZL2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Feb 22, 2019)
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no assertion criteria provided
Method: literature only
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DEAFNESS, AUTOSOMAL RECESSIVE 111
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000840383.2
First in ClinVar: Oct 19, 2018 Last updated: Feb 25, 2019 |
Comment on evidence:
In affected members of a consanguineous Dutch family (W05-682) segregating autosomal recessive deafness (DFNB111; 618145), Wesdorp et al. (2018) identified homozygosity for a 1-bp deletion … (more)
In affected members of a consanguineous Dutch family (W05-682) segregating autosomal recessive deafness (DFNB111; 618145), Wesdorp et al. (2018) identified homozygosity for a 1-bp deletion (c.72del, NM_005797.3) in the MPZL2 gene, resulting in a frameshift and a premature termination codon (Ile24MetfsTer22) in the signal domain of the protein. The mutation, which segregated with the phenotype in the family, was found by homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. By screening a phenotype-matched cohort and analysis of whole-exome sequencing data of a genetically undiagnosed cohort with hearing loss, Wesdorp et al. (2018) identified one Turkish family (W16-0195) homozygous for c.72del and another Turkish family (W16-9451) compound heterozygous for c.72del and c.220C-T in MPZL2, resulting in a gln74-to-ter substitution (604873.0002). The mutations segregated with the phenotype in both families. All of the mutations were confirmed by Sanger sequencing. The c.72del variant is found in heterozygous state at a global minor allele frequency of 0.00077 and an allele frequency of 0.00375 in the Ashkenazi Jewish population in the gnomAD database. The c.220C-T variant was found in heterozygous state at a global allele frequency of 0.00038 in the gnomAD database. In affected members of 3 consanguineous families from Turkey and Iran with DFNB111, Bademci et al. (2018) identified homozygosity for the c.72delA founder mutation in the MPZL2 gene. The mutation segregated with the phenotype in all families. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953019.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001967065.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss. | Bademci G | Human genetics | 2018 | PMID: 29982980 |
MPZL2, Encoding the Epithelial Junctional Protein Myelin Protein Zero-like 2, Is Essential for Hearing in Man and Mouse. | Wesdorp M | American journal of human genetics | 2018 | PMID: 29961571 |
Text-mined citations for rs752672077 ...
HelpRecord last updated Mar 17, 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.