VCV000008104.12 - ClinVar

NM_006261.5(PROP1):c.217C>T (p.Arg73Cys)

Germline

Classification

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.

(6)

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

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.217C>T (p.Arg73Cys)

Variation ID: 8104 Accession: VCV000008104.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q35.3 5: 177994231 (GRCh38) [ NCBI UCSC ] 5: 177421232 (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 17, 2014	Feb 14, 2024	Sep 19, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006261.5:c.217C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006252.4:p.Arg73Cys	missense
NC_000005.10:g.177994231G>A
NC_000005.9:g.177421232G>A
NG_015889.1:g.7012C>T
	O75360:p.Arg73Cys

... more HGVS ... less HGVS

Protein change

R73C

Other names

Canonical SPDI

NC_000005.10:177994230:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00003

Links

ClinGen: CA340733 UniProtKB: O75360#VAR_003768 OMIM: 601538.0010 dbSNP: rs121917843 VarSome

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
Gene	OMIM	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.
Pituitary hormone deficiency, combined, 2	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 19, 2023	RCV000008572.8
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 9, 2023	RCV000821200.7

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.
Pathogenic (Oct 11, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Pituitary hormone deficiency, combined, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000794668.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (4) PubMed: 15531542‚ 25557026‚ 16735499‚ 17526936
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pituitary hormone deficiency, combined, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813837.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pituitary hormone deficiency, combined, 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206530.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Sep 09, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000961949.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 9824293‚ 10946881‚ 11549703‚ 15531542‚ 25557026 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 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 73 of the PROP1 protein (p.Arg73Cys). This variant is present in population databases (rs121917843, gnomAD 0.004%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9824293, 10946881, 11549703, 15531542, 25557026). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8104). 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: 15531542, 25557026). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 01, 2004)	no assertion criteria provided Method: literature only	PITUITARY HORMONE DEFICIENCY, COMBINED, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028780.3 First in ClinVar: Apr 04, 2013 Last updated: Feb 03, 2020	Publications: PubMed (3) PubMed: 9824293‚ 11549703‚ 15531542 Comment on evidence: In 2 brothers from a consanguineous Tunisian family with combined pituitary hormone deficiency (CPHD2; 262600), Duquesnoy et al. (1998) identified a 217C-T transition in exon … (more) In 2 brothers from a consanguineous Tunisian family with combined pituitary hormone deficiency (CPHD2; 262600), Duquesnoy et al. (1998) identified a 217C-T transition in exon 2 of the PROP1 gene, resulting in an arg73-to-cys (R73C) substitution. The authors noted that arginine-73 is conserved in 95% of the more than 400 known homeodomain proteins. Vallette-Kasic et al. (2001) found the R73C mutation in homozygosity in 2 patients from 2 unrelated families, and in compound heterozygosity with R99X (601538.0011) in 1 patient. Reynaud et al. (2004) found this mutation in homozygosity on all affected members of a large consanguineous Tunisian kindred. Transfection studies demonstrated that the mutant protein had 11.5% of the transactivation capacity of the wildtype protein. No detectable DNA binding was observed with R73C in electromobility shift assays, whereas in vitro translated PROP1 and R73C proteins were similar in their expression and electrophoretic properties. (less)
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: SCV001452803.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the PROP1 protein (p.Arg73Cys). This variant is present in population databases (rs121917843, gnomAD 0.004%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9824293, 10946881, 11549703, 15531542, 25557026). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8104). 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: 15531542, 25557026). For these reasons, this variant has been classified as Pathogenic.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism.	Fritez N	Clinical endocrinology	2015	PMID: 25557026
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
A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.	Reynaud R	The Journal of clinical endocrinology and metabolism	2004	PMID: 15531542
PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.	Vallette-Kasic S	The Journal of clinical endocrinology and metabolism	2001	PMID: 11549703
Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.	Osorio MG	The Journal of clinical endocrinology and metabolism	2000	PMID: 10946881
Human Prop-1: cloning, mapping, genomic structure. Mutations in familial combined pituitary hormone deficiency.	Duquesnoy P	FEBS letters	1998	PMID: 9824293

Text-mined citations for rs121917843 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_006261.5(PROP1):c.217C>T (p.Arg73Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121917843 ...