ClinVar Genomic variation as it relates to human health
NM_004493.3(HSD17B10):c.388C>T (p.Arg130Cys)
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_004493.3(HSD17B10):c.388C>T (p.Arg130Cys)
Variation ID: 11442 Accession: VCV000011442.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp11.22 X: 53432086 (GRCh38) [ NCBI UCSC ] X: 53459034 (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 May 13, 2017 Dec 9, 2023 Jun 27, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004493.3:c.388C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004484.1:p.Arg130Cys missense NM_001037811.2:c.388C>T NP_001032900.1:p.Arg130Cys missense NC_000023.11:g.53432086G>A NC_000023.10:g.53459034G>A NG_008153.1:g.7290C>T NG_033076.2:g.14232G>A LRG_450:g.7290C>T LRG_450t1:c.388C>T LRG_450p1:p.Arg130Cys LRG_450t2:c.388C>T LRG_450p2:p.Arg130Cys Q99714:p.Arg130Cys - Protein change
- R130C
- Other names
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- Canonical SPDI
- NC_000023.11:53432085:G:A
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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.
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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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HSD17B10 | No evidence available | No evidence available |
GRCh38 GRCh37 |
164 | 323 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Feb 24, 2018 | RCV000012195.23 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 27, 2019 | RCV001224055.1 |
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
(Feb 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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HSD10 mitochondrial disease
Affected status: yes
Allele origin:
maternal
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244963.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A hemizygous missense variant, NM_001037811.2(HSD17B10):c.388C>T, has been identified in exon 4 of 6 of the HSD17B10 gene. The variant is predicted to result in a … (more)
A hemizygous missense variant, NM_001037811.2(HSD17B10):c.388C>T, has been identified in exon 4 of 6 of the HSD17B10 gene. The variant is predicted to result in a major amino acid change from arginine to cysteine at position 130 of the protein (NP_004484.1(HSD17B10):p.(Arg130Cys)). The arginine at this position has high conservation (100 vertebrates, UCSC), and is located within the short chain dehydrogenase functional domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic and has previously been reported as de-novo or maternally inherited in multiple families with HSD10 mitochondrial disease (ClinVar, OMIM, Zschocke J. (2012)). Additionally, immunoanalysis and studies of enzyme activity showed decreased amount of the enzyme and complete absence of enzyme activity (Yang S.Y., et al. (2009)). Analysis of parental samples indicated this variant to be maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Number of individuals with the variant: 2
Clinical Features:
Respiratory insufficiency (present) , Hypertonia (present) , Lactic acidosis (present)
Family history: yes
Secondary finding: no
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Pathogenic
(Jun 27, 2019)
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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: SCV001396232.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This sequence change replaces arginine with cysteine at codon 130 of the HSD17B10 protein (p.Arg130Cys). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with cysteine at codon 130 of the HSD17B10 protein (p.Arg130Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (PMID: 12696021, 18996107, 23266819). ClinVar contains an entry for this variant (Variation ID: 11442). This variant has been reported to affect HSD17B10 protein function (PMID: 12696021, 24549042). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 25, 2017)
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criteria provided, single submitter
Method: clinical testing
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HSD10 mitochondrial disease
(X-linked inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680262.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(Feb 01, 2010)
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no assertion criteria provided
Method: literature only
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HSD10 MITOCHONDRIAL DISEASE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032429.6
First in ClinVar: Apr 04, 2013 Last updated: Dec 09, 2023 |
Comment on evidence:
In 3 male patients with HSD10 mitochondrial disease (HSD10MD; 300438), Ofman et al. (2003) identified hemizygosity for a 388C-T transition in exon 4 of the … (more)
In 3 male patients with HSD10 mitochondrial disease (HSD10MD; 300438), Ofman et al. (2003) identified hemizygosity for a 388C-T transition in exon 4 of the HADH2 gene, resulting in an arg130-to-cys (R130C) substitution. All patients showed neurologic abnormalities, including psychomotor retardation and loss of mental and motor skills. The R130C mutation was found in the heterozygous state in a female patient, who had psychomotor retardation without loss of developmental milestones. Immunoanalysis and studies of enzyme activity showed decreased amount of the enzyme and complete absence of enzyme activity. The patients had previously been reported by Zschocke et al. (2000), Ensenauer et al. (2002), and Poll-The et al. (2001). Perez-Cerda et al. (2005) identified the R130C mutation in a Spanish boy with HSD10MD. He presented within the first hours of life with dehydration, hypoglycemia, and hypotonia. Despite institution of an isoleucine-restricted diet, he died at age 18 months. Laboratory analysis showed markedly decreased MHBD activity (0.8 nmol/min/mg protein, control value of 7.1). The patient's mother, who had borderline learning difficulties, also carried the mutation. Yang et al. (2009) identified the R130C substitution in a patient with HSD10MD reported by Sutton et al. (2003). The patient had a severe phenotype with seizures and visual loss, and died at age 10 years. Yang et al. (2009) stated that the R130C substitution resulted from a 419C-T transition in exon 4 of the HSD17B10 gene. Fibroblast HSD17B10 protein levels were about 50% of normal controls, but enzyme activity was less than 1.4% of normal values. In vitro functional expression assays showed that the mutant protein had almost no catalytic activity toward allopregnanolone or 2-methyl-3-hydroxybutyryl CoA. Yang et al. (2009) postulated that the neurologic phenotype was due to an imbalance in neurosteroid metabolism. Yang (2014) corrected the nucleotide transition to 388C-T. Rauschenberger et al. (2010) found that the R130C mutant protein, which was unstable at room temperature, lost enzymatic activity. Cells from a patient with the R130C mutation showed punctate and fragmented mitochondrial organization. Transfection of the R130C mutation into HSD17B10-null cells failed to rescue apoptosis. The findings suggested that the mutation causes a defect in mitochondrial function. (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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A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. | Rauschenberger K | EMBO molecular medicine | 2010 | PMID: 20077426 |
Study of patients and carriers with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: difficulties in the diagnosis. | García-Villoria J | Clinical biochemistry | 2009 | PMID: 18996107 |
HSD17B10: a gene involved in cognitive function through metabolism of isoleucine and neuroactive steroids. | Yang SY | Molecular genetics and metabolism | 2007 | PMID: 17618155 |
3-Hydroxyacyl-CoA dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase in human health and disease. | Yang SY | The FEBS journal | 2005 | PMID: 16176262 |
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiency: an X-linked inborn error of isoleucine metabolism that may mimic a mitochondrial disease. | Perez-Cerda C | Pediatric research | 2005 | PMID: 16148061 |
3-Hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency. | Sutton VR | Journal of inherited metabolic disease | 2003 | PMID: 12872843 |
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. | Ofman R | American journal of human genetics | 2003 | PMID: 12696021 |
Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency. | Ensenauer R | Annals of neurology | 2002 | PMID: 12112118 |
Progressive infantile neurodegeneration caused by 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency: a novel inborn error of branched-chain fatty acid and isoleucine metabolism. | Zschocke J | Pediatric research | 2000 | PMID: 11102558 |
Poll-The, B. T., Duran, M., Ruiter, J. P. N., Wanders, R. J. A., Barth, P. G. Mild cerebral white matter disease associated with 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 24: 59-only, 2001. | - | - | - | - |
Text-mined citations for rs28935475 ...
HelpRecord last updated Jul 29, 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.