Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 47 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31910894, 31447100, 31400068, 28475857, 25081361, 29704315)
ClinVar Genomic variation as it relates to human health
NM_005321.3(H1-4):c.441dup (p.Lys148fs)
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.
(10)
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
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005321.3(H1-4):c.441dup (p.Lys148fs)
Variation ID: 428606 Accession: VCV000428606.14
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 6p22.2 6: 26156826-26156827 (GRCh38) [ NCBI UCSC ] 6: 26157054-26157055 (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 Jul 1, 2017 Nov 17, 2024 Feb 23, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005321.3:c.441dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005312.1:p.Lys148fs frameshift NM_005321.3:c.441dupC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_005321.2:c.441dupC NC_000006.12:g.26156831dup NC_000006.11:g.26157059dup - Protein change
- K148fs
- Other names
- -
- Canonical SPDI
- NC_000006.12:26156826:CCCCC:CCCCCC
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| H1-4 | No evidence available | No evidence available |
GRCh38 GRCh37 |
163 | 179 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000492407.8 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 6, 2020 | RCV000782004.5 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 8, 2023 | RCV003984842.2 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jan 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV000920464.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
|
|
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Pathogenic
(May 01, 2019)
|
criteria provided, single submitter
Method: research
|
Rahman syndrome
Affected status: yes
Allele origin:
de novo
|
Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital
Accession: SCV000925236.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Rahman syndrome
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440316.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468922.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
|
|
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Pathogenic
(Apr 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001811898.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 47 incorrect amino … (more)
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 47 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31910894, 31447100, 31400068, 28475857, 25081361, 29704315) (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rahman syndrome
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841324.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000428606). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Increased body weight (present) , Panhypopituitarism (present)
|
|
|
Pathogenic
(Feb 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Rahman syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center
Accession: SCV005397415.1
First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024 |
Comment:
This sequence variant is a one-nucleotide duplication (dupC) at coding position 441 in the H1-4 gene. This variant has been referred to as c.437dupC and … (more)
This sequence variant is a one-nucleotide duplication (dupC) at coding position 441 in the H1-4 gene. This variant has been referred to as c.437dupC and c.441dup in the published literature. This duplication results in a premature termition sigl 48 codons downstream of the frameshift introduced at codon 148. This variant is absent from the gnomAD population database (0 of approximately 230,000 alleles). This is a previously reported variant (ClinVar) that has been identified in multiple D sequencing studies in individuals expressing variable clinical phenotypes including, but not limited to, intellectual disability, autism, microcephaly, seizures, brain atrophy, scoliosis, hip dislocation, dysmorphic features, hyperpigmented lesions in the trunk and distinctive facial gestalt (PMID: 28475857, 29704315, 31130284, 31400068). An in vitro functiol study showed that this variant disrupts proper compaction of D causing a dramatic reduction in proliferation rate and accelerated senescence of patient derived cultured cells (PMID: 31447100). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PS3, PS4, PVS1 (less)
|
|
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Pathogenic
(Jun 27, 2017)
|
no assertion criteria provided
Method: literature only
|
RAHMAN SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000580688.1
First in ClinVar: Jul 01, 2017 Last updated: Jul 01, 2017 |
Comment on evidence:
In 2 unrelated patients (COG0412 and COG0552) with Rahman syndrome (RMNS; 617537), aged 16 and 4 years, respectively, Tatton-Brown et al. (2017) identified a heterozygous … (more)
In 2 unrelated patients (COG0412 and COG0552) with Rahman syndrome (RMNS; 617537), aged 16 and 4 years, respectively, Tatton-Brown et al. (2017) identified a heterozygous 1-bp duplication (c.441dupC, NM_005321) in the HIST1H1E gene, resulting in a frameshift, premature termination, and generation of a truncated protein in the C-terminal domain. The mutation, which was found by whole-exome sequencing confirmed by Sanger sequencing, was not found in the ExAC database or in an in-house database of 11,677 exomes. The mutation occurred de novo in 1 patient; parental DNA from the other patient was not available. (less)
|
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Pathogenic
(Sep 13, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Rahman syndrome
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011701.1
First in ClinVar: Nov 05, 2021 Last updated: Nov 05, 2021 |
|
|
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Pathogenic
(Oct 08, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Auditory neuropathy spectrum disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Department of Otolaryngology, Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University
Accession: SCV004801121.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Family history: no
Age: 0-9 years
Sex: male
Ethnicity/Population group: Asian
Geographic origin: China
Tissue: Blood
|
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000428606). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence variant is a one-nucleotide duplication (dupC) at coding position 441 in the H1-4 gene. This variant has been referred to as c.437dupC and c.441dup in the published literature. This duplication results in a premature termition sigl 48 codons downstream of the frameshift introduced at codon 148. This variant is absent from the gnomAD population database (0 of approximately 230,000 alleles). This is a previously reported variant (ClinVar) that has been identified in multiple D sequencing studies in individuals expressing variable clinical phenotypes including, but not limited to, intellectual disability, autism, microcephaly, seizures, brain atrophy, scoliosis, hip dislocation, dysmorphic features, hyperpigmented lesions in the trunk and distinctive facial gestalt (PMID: 28475857, 29704315, 31130284, 31400068). An in vitro functiol study showed that this variant disrupts proper compaction of D causing a dramatic reduction in proliferation rate and accelerated senescence of patient derived cultured cells (PMID: 31447100). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PS3, PS4, PVS1
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:
Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 72 amino acids are lost and replaced with 47 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31910894, 31447100, 31400068, 28475857, 25081361, 29704315)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000428606). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence variant is a one-nucleotide duplication (dupC) at coding position 441 in the H1-4 gene. This variant has been referred to as c.437dupC and c.441dup in the published literature. This duplication results in a premature termition sigl 48 codons downstream of the frameshift introduced at codon 148. This variant is absent from the gnomAD population database (0 of approximately 230,000 alleles). This is a previously reported variant (ClinVar) that has been identified in multiple D sequencing studies in individuals expressing variable clinical phenotypes including, but not limited to, intellectual disability, autism, microcephaly, seizures, brain atrophy, scoliosis, hip dislocation, dysmorphic features, hyperpigmented lesions in the trunk and distinctive facial gestalt (PMID: 28475857, 29704315, 31130284, 31400068). An in vitro functiol study showed that this variant disrupts proper compaction of D causing a dramatic reduction in proliferation rate and accelerated senescence of patient derived cultured cells (PMID: 31447100). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PS3, PS4, PVS1
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging. | Flex E | American journal of human genetics | 2019 | PMID: 31447100 |
| HIST1H1E heterozygous protein-truncating variants cause a recognizable syndrome with intellectual disability and distinctive facial gestalt: A study to clarify the HIST1H1E syndrome phenotype in 30 individuals. | Burkardt DD | American journal of medical genetics. Part A | 2019 | PMID: 31400068 |
| Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
| Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review. | Duffney LJ | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2018 | PMID: 29704315 |
| Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability. | Tatton-Brown K | American journal of human genetics | 2017 | PMID: 28475857 |
Text-mined citations for rs1131690806 ...
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 Nov 19, 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.