ClinVar Genomic variation as it relates to human health
NM_015884.4(MBTPS2):c.1286G>A (p.Arg429His)
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_015884.4(MBTPS2):c.1286G>A (p.Arg429His)
Variation ID: 11404 Accession: VCV000011404.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: Xp22.12 X: 21880921 (GRCh38) [ NCBI UCSC ] X: 21899039 (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 4, 2013 Dec 31, 2022 Jan 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015884.4:c.1286G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056968.1:p.Arg429His missense NC_000023.11:g.21880921G>A NC_000023.10:g.21899039G>A NG_012797.2:g.46384G>A O43462:p.Arg429His - Protein change
- R429H
- Other names
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- Canonical SPDI
- NC_000023.11:21880920: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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MBTPS2 | - | - |
GRCh38 GRCh37 |
153 | 341 |
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 (2) |
criteria provided, single submitter
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Jan 3, 2022 | RCV000012157.30 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2019 | RCV000081781.18 |
Submissions - Germline
Classification
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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
(Jul 23, 2012)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000113716.8
First in ClinVar: Jan 17, 2014 Last updated: Mar 08, 2017 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Oct 04, 2019)
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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: SCV000321866.6
First in ClinVar: Oct 09, 2016 Last updated: Mar 08, 2017 |
Comment:
Published functional studies demonstrate reduced enzymatic activity of the MBTPS2 protein, with variants such as R429H that are closer to the intramembranous domain being more … (more)
Published functional studies demonstrate reduced enzymatic activity of the MBTPS2 protein, with variants such as R429H that are closer to the intramembranous domain being more detrimental than missense changes in the amino-terminal portion of the protein (Oeffner et al., 2009; Bornholdt et al; 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19361614, 23316014, 22105905, 21179107, 27380894, 27663151, 26762237, 33258288) (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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IFAP syndrome 1, with or without BRESHECK syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058770.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 19361614, 23316014, PS4_S). Functional studies provide strong evidence of the variant having a … (more)
The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 19361614, 23316014, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19361614, 23316014, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.963, PP3_P). A missense variant is a common mechanism associated with IFAP syndrome with or without BRESHECK syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Ectodermal dysplasia (present) , Split hand (present) , Seizure (present) , Growth delay (present) , Nail dystrophy (present) , Dry skin (present) , Macular dystrophy … (more)
Ectodermal dysplasia (present) , Split hand (present) , Seizure (present) , Growth delay (present) , Nail dystrophy (present) , Dry skin (present) , Macular dystrophy (present) (less)
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Pathogenic
(Jan 01, 2012)
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no assertion criteria provided
Method: literature only
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IFAP SYNDROME 1 WITH BRESHECK SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032391.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 31, 2022 |
Comment on evidence:
In affected members of a 3-generation pedigree segregating IFAP syndrome with additional features consistent with BRESHECK syndrome (IFAP1; 308205), Oeffner et al. (2009) identified a … (more)
In affected members of a 3-generation pedigree segregating IFAP syndrome with additional features consistent with BRESHECK syndrome (IFAP1; 308205), Oeffner et al. (2009) identified a 1286G-A transition in the MBTPS2 gene, resulting in an arg429-to-his (R429H) substitution. The mutation was not identified in 225 X chromosomes from unrelated individuals. Male patients had a severe form of the disorder, with multiple additional malformations and death within 2 years of birth. One male was a collodion baby who also had cleft palate, unilateral cleft hand, 2 butterfly vertebrae, absence of a kidney, and bilateral inguinal hernia, omphalocele, stenosis of small intestine, and Hirschsprung disease. Another had IFAP triad, microcephaly, arachnoid cyst, Arnold-Chiari malformation type I, thoracolumbar hydromyelia, seizures, psychomotor retardation, retrognathia, deficient growth, cleft hands, butterfly vertebra, wedge-shaped vertebra, atrial septal defect, arterial hypertension, recurrent infections of upper airways, absence of a kidney, hypospadias, choanal stenosis, inguinal hernia, and Hirschsprung disease Obligate carrier females were either phenotypically normal or mildly affected. Functional studies with this mutation showed almost no MBTPS2 activity. In a Japanese boy with a clinical diagnosis of BRESHECK syndrome, Naiki et al. (2012) identified an R429H mutation in the MBTPS2 gene (300294.0003). His unaffected mother was heterozygous for the mutation. The patient had multiple severe congenital anomalies, including generalized alopecia, erythematous skin with continuous desquamation, photophobia, corneal erosions, dystrophic nails, hearing loss, and severely delayed psychomotor development. He also had Hirschsprung disease, imbalanced hemivertebrae in the 2 lowest thoracic vertebral bodies, and a small right kidney. Brain MRI at age 3 showed decreased volumes of the frontal and parietal lobes, thinning of the corpus callosum, and ventricular dilatation. At 4 years of age, he was bedridden and showed almost no response to people. The same mutation had previously been reported in a patient with severe IFAP (Oeffner et al., 2009), indicating that the 2 disorders are allelic and represent a phenotypic spectrum. In a 5-month-old Portuguese boy with severe findings of IFAP1/BRESHECK syndrome, Corujeira et al. (2013) identified the R429H mutation in the MBTPS2 gene. In addition to typical features of the disorder, including ichthyosis follicularis, atrichia, photophobia, brain anomalies, global developmental delay, Hirschsprung disease, and kidney hypoplasia, the patient had severe hypogammaglobulinemia and congenital rectourethral fistula. Corujeira et al. (2013) noted that among the 6 reported patients (including theirs) with the R429H mutation, 4 had Hirschsprung disease; they proposed that this defect might be a phenotypic marker for this variant since other patients with IFAP/BRESHECK syndrome do not have Hirschsprung disease. (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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Expanding the phenotype of IFAP/BRESECK syndrome: a new case with severe hypogammaglobulinemia. | Corujeira S | European journal of medical genetics | 2013 | PMID: 24090718 |
Genotype-phenotype correlations emerging from the identification of missense mutations in MBTPS2. | Bornholdt D | Human mutation | 2013 | PMID: 23316014 |
MBTPS2 mutation causes BRESEK/BRESHECK syndrome. | Naiki M | American journal of medical genetics. Part A | 2012 | PMID: 22105905 |
IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. | Oeffner F | American journal of human genetics | 2009 | PMID: 19361614 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MBTPS2 | - | - | - | - |
Text-mined citations for rs122468178 ...
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.