ClinVar Genomic variation as it relates to human health
NM_001378414.1(HDAC4):c.743C>T (p.Pro248Leu)
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.
Pathogenic(4); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001378414.1(HDAC4):c.743C>T (p.Pro248Leu)
Variation ID: 424498 Accession: VCV000424498.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q37.3 2: 239144705 (GRCh38) [ NCBI UCSC ] 2: 240066401 (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 Apr 29, 2017 May 1, 2024 Sep 7, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001378414.1:c.743C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365343.1:p.Pro248Leu missense NM_001378415.1:c.743C>T NP_001365344.1:p.Pro248Leu missense NM_001378416.1:c.743C>T NP_001365345.1:p.Pro248Leu missense NM_001378417.1:c.743C>T NP_001365346.1:p.Pro248Leu missense NM_006037.4:c.743C>T NP_006028.2:p.Pro248Leu missense NC_000002.12:g.239144705G>A NC_000002.11:g.240066401G>A NG_009235.1:g.261243C>T - Protein change
- P248L
- Other names
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- Canonical SPDI
- NC_000002.12:239144704:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- gain_of_function_variant Sequence Ontology [SO:0002053]
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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.
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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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HDAC4 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
482 | 586 |
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
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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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Nov 26, 2018 | RCV000486144.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2023 | RCV000622488.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 3, 2020 | RCV001290415.2 | |
not provided (1) |
no classification provided
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- | RCV001824806.1 | |
Uncertain significance (2) |
criteria provided, single submitter
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May 21, 2020 | RCV001849182.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 21, 2021 | RCV002286740.1 |
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
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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Pathogenic
(Nov 26, 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: SCV000574314.5
First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019 |
Comment:
The P248L variant in the HDAC4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more)
The P248L variant in the HDAC4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P248L variant is not observed in large population cohorts (Lek et al., 2016). The P248L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P248L as a pathogenic variant. (less)
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Pathogenic
(Sep 07, 2023)
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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: SCV000741300.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.743C>T (p.P248L) alteration is located in exon 8 (coding exon 7) of the HDAC4 gene. This alteration results from a C to T substitution … (more)
The c.743C>T (p.P248L) alteration is located in exon 8 (coding exon 7) of the HDAC4 gene. This alteration results from a C to T substitution at nucleotide position 743, causing the proline (P) at amino acid position 248 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant and another alteration at the same codon, c.742C>G (p.P248A), have been determined to be the result of a de novo mutation in multiple individuals with features consistent with HDAC4-related neurodevelopmental disorder (Wakeling, 2021). This amino acid position is highly conserved in available vertebrate species. The p.P248L amino acid is located within the nuclear localization domain and is an important residue for protein binding and HDAC4 export from the nucleus. The location of this alteration is 2 amino acids away from a phosphorylated serine (p.S246), the phosphorylation of which is required for export of HDAC4 from the nucleus (Wang, 2001). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Pathogenic
(Aug 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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Intellectual disability, profound
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV001427054.1
First in ClinVar: Feb 12, 2021 Last updated: Feb 12, 2021 |
Number of individuals with the variant: 5
Clinical Features:
Intellectual disability (present) , Generalized hypotonia (present) , apnea (present) , poor feeding (present) , difficulty swallowing (present) , neurogenerative process (present) , Seizures (present)
Sex: mixed
Comment on evidence:
In this group of patients are5 individuals: DECIPHER 275175, DECIPHER 286901, ClinVar SCV000741300.1, ClinVar SCV000574314.5, plus one additional female patient described here.
Testing laboratory: Baylor Genetics
Date variant was reported to submitter: 2019-04-08
Testing laboratory interpretation: not provided
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Pathogenic
(Dec 21, 2021)
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criteria provided, single submitter
Method: clinical testing
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Chromosome 2q37 deletion syndrome
Affected status: yes
Allele origin:
de novo
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV002577476.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
PS2, PM1, PM2, PP3, PP5
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Uncertain significance
(May 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurodevelopmental disorder with central hypotonia and dysmorphic facies
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769311.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A - VUS. Following criteria are met: 0105 - The mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A - VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a proline to a leucine (exon 8). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0704 – A comparable variant (p.Pro248Ala) has low previous evidence for pathogenicity in a single patient with intellectual disability and joint laxity (Decipher). (P) 0802 - Moderate previous evidence of pathogenicity in three unrelated individuals with intellectual disability and joint laxity (Decipher, ClinVar). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Mar 18, 2022)
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no assertion criteria provided
Method: literature only
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NEURODEVELOPMENTAL DISORDER WITH CENTRAL HYPOTONIA AND DYSMORPHIC FACIES
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV002106384.1
First in ClinVar: Mar 23, 2022 Last updated: Mar 23, 2022 |
Comment on evidence:
In 4 unrelated patients (patients 4-7) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo … (more)
In 4 unrelated patients (patients 4-7) with neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF; 619797), Wakeling et al. (2021) identified a de novo heterozygous c.743C-T transition (c.743C-T, NM_006037.4) in the HDAC4 gene, resulting in a pro248-to-leu (P248L) substitution at a conserved site. The mutation, which was identified by whole-exome sequencing, was not present in the gnomAD database. he mutation is located in the HDAC4 14-3-3 binding site and is predicted to result in decreased binding of 14-3-3 proteins. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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Brachydactyly syndrome type E
Affected status: yes
Allele origin:
de novo
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GenomeConnect, ClinGen
Accession: SCV002074870.1
First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022 |
Comment:
Multiple laboratories identified the variant in this registry participant. Variant interpreted as Pathogenic and reported, most recently, on 03-29-2019 by Lab or GTR ID 26957. … (more)
Multiple laboratories identified the variant in this registry participant. Variant interpreted as Pathogenic and reported, most recently, on 03-29-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Abnormality of the nervous system (present) , Cognitive impairment … (more)
Abnormality of the amniotic fluid (present) , Abnormality of eye movement (present) , Hypermetropia (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Abnormal morphology of the pelvis musculature (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2019-03-29
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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gain_of_function_variant
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Elsea Laboratory, Baylor College of Medicine
Accession: SCV001427054.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. | Wakeling E | HGG advances | 2021 | PMID: 33537682 |
Histone deacetylase 4 possesses intrinsic nuclear import and export signals. | Wang AH | Molecular and cellular biology | 2001 | PMID: 11486037 |
Text-mined citations for rs1064797002 ...
HelpRecord last updated May 01, 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.