This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 16 of the ZMYND10 protein (p.Val16Gly). This variant is present in population databases (rs138815960, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23891469, 23891471). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66021). 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 ZMYND10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ZMYND10 function (PMID: 23891471). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_015896.4(ZMYND10):c.47T>G (p.Val16Gly)
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.
(11)
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
11
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015896.4(ZMYND10):c.47T>G (p.Val16Gly)
Variation ID: 66021 Accession: VCV000066021.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p21.31 3: 50345533 (GRCh38) [ NCBI UCSC ] 3: 50382964 (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 Sep 29, 2015 Oct 20, 2024 Dec 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015896.4:c.47T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056980.2:p.Val16Gly missense NM_001308379.2:c.47T>G NP_001295308.1:p.Val16Gly missense NM_015896.3:c.47T>G NC_000003.12:g.50345533A>C NC_000003.11:g.50382964A>C NG_023270.1:g.404T>G NG_042828.1:g.5214T>G O75800:p.Val16Gly - Protein change
- V16G
- Other names
-
ZMYND10, VAL16GLY (rs138815960)
- Canonical SPDI
- NC_000003.12:50345532:A:C
-
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) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00024
The Genome Aggregation Database (gnomAD), exomes 0.00027
Exome Aggregation Consortium (ExAC) 0.00049
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
- 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. |
|||
| ZMYND10 | - | - |
GRCh38 GRCh37 |
210 | 222 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 7, 2023 | RCV000056264.16 | |
| not provided (1) |
no classification provided
|
- | RCV000190919.10 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 11, 2023 | RCV000459281.18 | |
|
ZMYND10-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 19, 2024 | RCV004754290.1 |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 20, 2023 | RCV001090588.29 |
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
(Mar 21, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448837.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Depressivity (present) , Intellectual disability, borderline (present) , Attention deficit hyperactivity disorder (present) , Short stature (present) , Oppositional defiant disorder (present) , Specific learning … (more)
Depressivity (present) , Intellectual disability, borderline (present) , Attention deficit hyperactivity disorder (present) , Short stature (present) , Oppositional defiant disorder (present) , Specific learning disability (present) , Behavioral abnormality (present) (less)
Sex: male
|
|
|
Pathogenic
(Jun 25, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 22
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020943.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551460.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 16 of the ZMYND10 protein (p.Val16Gly). … (more)
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 16 of the ZMYND10 protein (p.Val16Gly). This variant is present in population databases (rs138815960, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23891469, 23891471). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66021). 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 ZMYND10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ZMYND10 function (PMID: 23891471). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia 22
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV003927224.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
This ZMYND10 missense variant has been reported to occur in the homozygous or compound heterozygous state in unrelated individuals and families with primary ciliary dyskinesia. … (more)
This ZMYND10 missense variant has been reported to occur in the homozygous or compound heterozygous state in unrelated individuals and families with primary ciliary dyskinesia. This variant (rs138815960) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 67/272444 total alleles; 0.025%; no homozygotes), and has been reported in ClinVar6 (Variation ID 66021). Two bioinformatic tools queried predict that this substitution would be damaging, and the valine residue at this position is evolutionarily conserved across many of the species assessed. We consider c.47T>G;p.Val16Gly in ZMYND10 to be pathogenic. (less)
|
|
|
Pathogenic
(Dec 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary ciliary dyskinesia
Affected status: yes
Allele origin:
germline
|
Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre
Accession: SCV004176744.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
ACMG: PP5, PM2, PM3. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 66021)
Number of individuals with the variant: 1
Age: 20-29 years
Sex: male
Ethnicity/Population group: European Caucasoid
|
|
|
Pathogenic
(Jun 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199022.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jul 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001246204.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 08, 2013)
|
no assertion criteria provided
Method: literature only
|
CILIARY DYSKINESIA, PRIMARY, 22
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000087436.2
First in ClinVar: Nov 21, 2013 Last updated: May 01, 2017 |
Comment on evidence:
In a patient with primary ciliary dyskinesia-22 (CILD22; 615444) and situs inversus, Zariwala et al. (2013) identified a homozygous c.47T-G transversion in exon 1 of … (more)
In a patient with primary ciliary dyskinesia-22 (CILD22; 615444) and situs inversus, Zariwala et al. (2013) identified a homozygous c.47T-G transversion in exon 1 of the ZMYND10 gene, resulting in a val16-to-gly (V16G) substitution at a conserved residue. Video microscopy of patient respiratory cells showed immotile cilia, and electron microscopy showed outer and inner dynein arm defects. In 3 patients from 2 unrelated families of northern European descent with CILD22, Moore et al. (2013) identified a homozygous V16G (rs138815960) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The V16G variant was present in 6 of 4,300 European control exomes from the NHLBI Exome Sequencing Project Exome Variant Server, corresponding to a frequency of 0.000698; the variant was absent from 700 in-house control exomes. The clinical features were available for 1 of the homozygous patients. She had recurrent respiratory infections from birth, persistent rhinitis, recurrent otitis media, and bronchiectasis. Light microscopy of respiratory epithelial cells from this patient showed cilia with slowed frequency and stiff beat, and electron microscopy showed reduced, but not absent, inner and outer dynein arms. Two additional unrelated patients with CILD22 were compound heterozygous for V16G and another pathogenic mutation in the ZMYND10 gene (see, e.g., 607070.0006). Haplotype analysis suggested a founder effect among these patients. Transfection of the corresponding mutation (V14G) in Drosophila restored fertility in a mutant model, but not as fully as transfection with the wildtype protein. The findings suggested that the V16G allele may retain some function. (less)
|
|
|
Pathogenic
(Oct 09, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Primary ciliary dyskinesia 22
Affected status: yes
Allele origin:
germline
|
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Accession: SCV004041641.1
First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023 |
|
|
|
Pathogenic
(Jun 19, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ZMYND10-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005359201.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ZMYND10 c.47T>G variant is predicted to result in the amino acid substitution p.Val16Gly. This variant has been reported in the homozygous and compound heterozygous … (more)
The ZMYND10 c.47T>G variant is predicted to result in the amino acid substitution p.Val16Gly. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with primary ciliary dyskinesia with or without situs inversus (Moore et al. 2013. PubMed ID: 23891471; Zariwala et al. 2013. PubMed ID: 23891469). This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Kartagener syndrome
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000245805.2
First in ClinVar: Sep 29, 2015 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This ZMYND10 missense variant has been reported to occur in the homozygous or compound heterozygous state in unrelated individuals and families with primary ciliary dyskinesia. This variant (rs138815960) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 67/272444 total alleles; 0.025%; no homozygotes), and has been reported in ClinVar6 (Variation ID 66021). Two bioinformatic tools queried predict that this substitution would be damaging, and the valine residue at this position is evolutionarily conserved across many of the species assessed. We consider c.47T>G;p.Val16Gly in ZMYND10 to be pathogenic.
Comment:
ACMG: PP5, PM2, PM3. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 66021)
Comment:
The ZMYND10 c.47T>G variant is predicted to result in the amino acid substitution p.Val16Gly. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with primary ciliary dyskinesia with or without situs inversus (Moore et al. 2013. PubMed ID: 23891471; Zariwala et al. 2013. PubMed ID: 23891469). This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted 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:
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 16 of the ZMYND10 protein (p.Val16Gly). This variant is present in population databases (rs138815960, gnomAD 0.05%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 23891469, 23891471). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 66021). 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 ZMYND10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ZMYND10 function (PMID: 23891471). For these reasons, this variant has been classified as Pathogenic.
Comment:
This ZMYND10 missense variant has been reported to occur in the homozygous or compound heterozygous state in unrelated individuals and families with primary ciliary dyskinesia. This variant (rs138815960) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 67/272444 total alleles; 0.025%; no homozygotes), and has been reported in ClinVar6 (Variation ID 66021). Two bioinformatic tools queried predict that this substitution would be damaging, and the valine residue at this position is evolutionarily conserved across many of the species assessed. We consider c.47T>G;p.Val16Gly in ZMYND10 to be pathogenic.
Comment:
ACMG: PP5, PM2, PM3. The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 66021)
Comment:
The ZMYND10 c.47T>G variant is predicted to result in the amino acid substitution p.Val16Gly. This variant has been reported in the homozygous and compound heterozygous state in multiple unrelated individuals with primary ciliary dyskinesia with or without situs inversus (Moore et al. 2013. PubMed ID: 23891471; Zariwala et al. 2013. PubMed ID: 23891469). This variant is reported in 0.048% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Defects in the cytoplasmic assembly of axonemal dynein arms cause morphological abnormalities and dysmotility in sperm cells leading to male infertility. | Aprea I | PLoS genetics | 2021 | PMID: 33635866 |
| Primary Ciliary Dyskinesia. | Adam MP | - | 2019 | PMID: 20301301 |
| Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia. | Marshall CR | G3 (Bethesda, Md.) | 2015 | PMID: 26139845 |
| Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. | Moore DJ | American journal of human genetics | 2013 | PMID: 23891471 |
| ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. | Zariwala MA | American journal of human genetics | 2013 | PMID: 23891469 |
Text-mined citations for rs138815960 ...
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 Dec 07, 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.