NM_006261.4(PROP1):c.150delA(R53Dfs*112) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1-related. Sources cited for classification include the following: PMID 17526936, 15472232, 15126542, 11549674, 26608600, 26886902 and 22024773. Classification of NM_006261.4(PROP1):c.150delA(R53Dfs*112) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
ClinVar Genomic variation as it relates to human health
NM_006261.5(PROP1):c.150del (p.Arg53fs)
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.
(13)
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.
Conflicting classifications of pathogenicity
Pathogenic(9); Uncertain significance(1)
Pathogenic(9); Uncertain significance(1)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006261.5(PROP1):c.150del (p.Arg53fs)
Variation ID: 8102 Accession: VCV000008102.29
- Type and length
-
Deletion, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177994298 (GRCh38) [ NCBI UCSC ] 5: 177421299 (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 May 18, 2014 Aug 25, 2024 Mar 27, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006261.5:c.150del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006252.4:p.Arg53fs frameshift NM_006261.5:c.150delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
frameshift NM_006261.4:c.150delA NC_000005.10:g.177994298del NC_000005.9:g.177421299del NG_015889.1:g.6945del - Protein change
- R53fs
- Other names
- -
- Canonical SPDI
- NC_000005.10:177994297:T:
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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) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00009
Exome Aggregation Consortium (ExAC) 0.00013
- 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. |
|||
| PROP1 | - | - |
GRCh38 GRCh38 GRCh38 GRCh37 |
275 | 326 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000008570.29 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 28, 2024 | RCV001053115.17 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 8, 2021 | RCV004584320.1 |
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
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
(Dec 26, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193998.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020 |
Comment:
NM_006261.4(PROP1):c.150delA(R53Dfs*112) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1-related. Sources cited for classification include the following: PMID 17526936, 15472232, 15126542, … (more)
NM_006261.4(PROP1):c.150delA(R53Dfs*112) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1-related. Sources cited for classification include the following: PMID 17526936, 15472232, 15126542, 11549674, 26608600, 26886902 and 22024773. Classification of NM_006261.4(PROP1):c.150delA(R53Dfs*112) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Apr 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366332.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
|
|
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572789.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Frameshift variant is predicted to result in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with PROP1 -related disorder (ClinVar ID: VCV000008102 / PMID: 30266296). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypopituitarism (present) , Pituitary hypothyroidism (present) , Congenital isolated adrenocorticotropic hormone deficiency (present)
|
|
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Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009562.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Pituitary hormone deficiency, combined, 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV005038692.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
|
|
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Pathogenic
(Mar 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
see cases
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002506432.2
First in ClinVar: May 07, 2022 Last updated: Jul 07, 2024 |
Comment:
ACMG categories: PVS1,PS4,PM4,PP5
Number of individuals with the variant: 1
Clinical Features:
Panhypopituitarism (present)
Age: 30-39 years
Sex: male
Tissue: blood
|
|
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Pathogenic
(Jul 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005197278.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001217359.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg53Aspfs*112) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Arg53Aspfs*112) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 174 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs587776683, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with combined pituitary hormone deficiency (PMID: 15472232, 16735499, 21863341, 26608600, 28734020, 30266296). ClinVar contains an entry for this variant (Variation ID: 8102). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PROP1 function (PMID: 16735499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Pituitary hormone deficiency, combined, 2
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051945.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206523.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Sep 01, 2001)
|
no assertion criteria provided
Method: literature only
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PITUITARY HORMONE DEFICIENCY, COMBINED, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028778.3
First in ClinVar: Apr 04, 2013 Last updated: Feb 03, 2020 |
Comment on evidence:
In 2 brothers with combined pituitary hormone deficiency involving GH, TSH, PRL, and gonadotropins (CPHD2; 262600), who later also developed deficiencies of ACTH and cortisol … (more)
In 2 brothers with combined pituitary hormone deficiency involving GH, TSH, PRL, and gonadotropins (CPHD2; 262600), who later also developed deficiencies of ACTH and cortisol secretion, Riepe et al. (2001) identified compound heterozygosity for a 1-bp deletion (150delA) in the PROP1 gene and a 2-bp deletion (301delAG; 601538.0002). Both patients showed early pituitary enlargement by MRI, followed by subsequent marked hypoplasia. (less)
|
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Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Combined pituitary hormone deficiency type 2
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001452805.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002500844.2
First in ClinVar: Apr 23, 2022 Last updated: Oct 01, 2022 |
Comment:
There are reports of spontaneous puberty with decline of gonadotropic function in individuals with PROP1 variants p.Arg120Cys, p.Phe88Ser, and c.150delA [Flück et al 1998].
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Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with PROP1 -related disorder (ClinVar ID: VCV000008102 / PMID: 30266296). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ACMG categories: PVS1,PS4,PM4,PP5
Comment:
This sequence change creates a premature translational stop signal (p.Arg53Aspfs*112) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 174 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs587776683, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with combined pituitary hormone deficiency (PMID: 15472232, 16735499, 21863341, 26608600, 28734020, 30266296). ClinVar contains an entry for this variant (Variation ID: 8102). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PROP1 function (PMID: 16735499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
There are reports of spontaneous puberty with decline of gonadotropic function in individuals with PROP1 variants p.Arg120Cys, p.Phe88Ser, and c.150delA [Flück et al 1998].
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:
NM_006261.4(PROP1):c.150delA(R53Dfs*112) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1-related. Sources cited for classification include the following: PMID 17526936, 15472232, 15126542, 11549674, 26608600, 26886902 and 22024773. Classification of NM_006261.4(PROP1):c.150delA(R53Dfs*112) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with PROP1 -related disorder (ClinVar ID: VCV000008102 / PMID: 30266296). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ACMG categories: PVS1,PS4,PM4,PP5
Comment:
This sequence change creates a premature translational stop signal (p.Arg53Aspfs*112) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 174 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs587776683, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with combined pituitary hormone deficiency (PMID: 15472232, 16735499, 21863341, 26608600, 28734020, 30266296). ClinVar contains an entry for this variant (Variation ID: 8102). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PROP1 function (PMID: 16735499). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
There are reports of spontaneous puberty with decline of gonadotropic function in individuals with PROP1 variants p.Arg120Cys, p.Phe88Ser, and c.150delA [Flück et al 1998].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| PROP1-Related Combined Pituitary Hormone Deficiency. | Adam MP | - | 2022 | PMID: 20301521 |
| Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes. | Blum WF | EBioMedicine | 2018 | PMID: 30266296 |
| Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations. | Madeira JL | Clinical endocrinology | 2017 | PMID: 28734020 |
| Cancerous leptomeningitis and familial congenital hypopituitarism. | Vujovic S | Endocrine | 2016 | PMID: 26886902 |
| Two coexisting heterozygous frameshift mutations in PROP1 are responsible for a different phenotype of combined pituitary hormone deficiency. | Ziemnicka K | Journal of applied genetics | 2016 | PMID: 26608600 |
| Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations. | Dusatkova P | European journal of human genetics : EJHG | 2016 | PMID: 26059845 |
| Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects. | Obermannova B | Hormone research in paediatrics | 2011 | PMID: 22024773 |
| Case seminar: a young female with acute hyponatremia and a sellar mass. | Pekic S | Endocrine | 2011 | PMID: 21863341 |
| High prevalence of PROP1 gene mutations in Hungarian patients with childhood-onset combined anterior pituitary hormone deficiency. | Halász Z | Endocrine | 2006 | PMID: 17526936 |
| Genetic screening of combined pituitary hormone deficiency: experience in 195 patients. | Reynaud R | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16735499 |
| PROP1 mutations cause progressive deterioration of anterior pituitary function including adrenal insufficiency: a longitudinal analysis. | Böttner A | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15472232 |
| Pituitary magnetic resonance imaging in 15 patients with Prop1 gene mutations: pituitary enlargement may originate from the intermediate lobe. | Voutetakis A | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15126542 |
| Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation. | Riepe FG | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11549674 |
| Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C). | Flück C | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9768691 |
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Text-mined citations for rs587776683 ...
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 25, 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.