This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 120 of the PROP1 protein (p.Arg120Cys). This variant is present in population databases (rs121917839, gnomAD 0.03%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9462743, 9768691, 12153609, 17526949). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROP1 protein function. Experimental studies have shown that this missense change affects PROP1 function (PMID: 9462743). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_006261.5(PROP1):c.358C>T (p.Arg120Cys)
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.
(8)
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/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006261.5(PROP1):c.358C>T (p.Arg120Cys)
Variation ID: 8095 Accession: VCV000008095.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177993032 (GRCh38) [ NCBI UCSC ] 5: 177420033 (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 Mar 29, 2015 Jun 17, 2024 Mar 22, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_006261.5:c.358C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006252.4:p.Arg120Cys missense NC_000005.10:g.177993032G>A NC_000005.9:g.177420033G>A NG_015889.1:g.8211C>T O75360:p.Arg120Cys - Protein change
- R120C
- Other names
- -
- Canonical SPDI
- NC_000005.10:177993031:G:A
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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) 0.00005
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00007
- 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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 22, 2024 | RCV000008563.19 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2024 | RCV001389806.6 |
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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Likely pathogenic
(Apr 09, 2014)
|
criteria provided, single submitter
Method: literature only
|
Pituitary hormone deficiency, combined 2
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220236.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Mar 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810297.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591287.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 120 of the PROP1 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 120 of the PROP1 protein (p.Arg120Cys). This variant is present in population databases (rs121917839, gnomAD 0.03%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9462743, 9768691, 12153609, 17526949). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROP1 protein function. Experimental studies have shown that this missense change affects PROP1 function (PMID: 9462743). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Oct 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001934228.1
First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021 |
Comment:
This variant was identified as compound heterozygous with NM_006261.4:c.301_302del.
|
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Pathogenic
(Apr 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004170463.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Published functional studies demonstrate a decreased DNA binding efficiency (PMID: 9462743); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Published functional studies demonstrate a decreased DNA binding efficiency (PMID: 9462743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 12153609, 14614227, 33098107, 9462743, 9768691, 10323394, 17526949) (less)
|
|
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Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206524.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Oct 01, 1998)
|
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: SCV000028771.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 24, 2015 |
Comment on evidence:
In a family with 2 brothers and a sister with combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified a C-to-T transition resulting … (more)
In a family with 2 brothers and a sister with combined pituitary hormone deficiency (CPHD2; 262600), Wu et al. (1998) identified a C-to-T transition resulting in an arg120-to-cys amino acid substitution. In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene. The authors noted that there was variability in the phenotype, even among these patients with the same mutation. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Pituitary hormone deficiency, combined, 2
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV002500846.2
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].
|
Comment:
Comment:
This variant was identified as compound heterozygous with NM_006261.4:c.301_302del.
Comment:
Published functional studies demonstrate a decreased DNA binding efficiency (PMID: 9462743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 12153609, 14614227, 33098107, 9462743, 9768691, 10323394, 17526949)
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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 120 of the PROP1 protein (p.Arg120Cys). This variant is present in population databases (rs121917839, gnomAD 0.03%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9462743, 9768691, 12153609, 17526949). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROP1 protein function. Experimental studies have shown that this missense change affects PROP1 function (PMID: 9462743). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was identified as compound heterozygous with NM_006261.4:c.301_302del.
Comment:
Published functional studies demonstrate a decreased DNA binding efficiency (PMID: 9462743); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 12153609, 14614227, 33098107, 9462743, 9768691, 10323394, 17526949)
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 |
| The natural history of the R120C PROP1 mutation reveals a wide phenotypic variability in two untreated adult brothers with combined pituitary hormone deficiency. | Vieira TC | Endocrine | 2006 | PMID: 17526949 |
| PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency. | Lemos MC | Clinical endocrinology | 2006 | PMID: 16984240 |
| PROP-1 gene mutation (R120C) causing combined pituitary hormone deficiencies with variable clinical course in eight siblings of one Jewish Moroccan family. | Lazar L | Hormone research | 2003 | PMID: 14614227 |
| A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty. | Arroyo A | Clinical endocrinology | 2002 | PMID: 12153609 |
| "Hot spot" in the PROP1 gene responsible for combined pituitary hormone deficiency. | Deladoëy J | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10323394 |
| 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 |
| Mutations in PROP1 cause familial combined pituitary hormone deficiency. | Wu W | Nature genetics | 1998 | PMID: 9462743 |
Text-mined citations for rs121917839 ...
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 Sep 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.