rs587776683

Variant names:

• chr5-177994297-CT-C
• rs587776683
• NM_006261.5:c.150delA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006261.5(PROP1):​c.150delA​(p.Arg53AspfsTer112) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,611,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: PROP1 NM_006261.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1 O:1
• Conservation: PhyloP100: -0.0950

Genes affected

PROP1 (HGNC:9455): (PROP paired-like homeobox 1) This gene encodes a paired-like homeodomain transcription factor in the developing pituitary gland. Expression occurs prior to and is required for expression of pou domain transcription factor 1, which is responsible for pituitary development and hormone expression. Mutations in this gene have been associated with combined pituitary hormone deficiency-2 as well as deficiencies in luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, and thyroid-stimulating hormone. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.78 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177994297-CT-C is Pathogenic according to our data. Variant chr5-177994297-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 8102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177994297-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.150delA	p.Arg53AspfsTer112	frameshift_variant	Exon 2 of 3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.150delA	p.Arg53AspfsTer112	frameshift_variant	Exon 2 of 3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000863 AC: 21 AN: 243216 Hom.: 0 AF XY: 0.0000984 AC XY: 13 AN XY: 132082

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000610 AC: 89 AN: 1459676 Hom.: 0 Cov.: 32 AF XY: 0.0000703 AC XY: 51 AN XY: 725922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000774

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Pathogenic:10 Other:1

Dec 26, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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]. -

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 12, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 08, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2 Uncertain:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 gene product 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. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Jul 04, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Mar 08, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PS4,PM4,PP5 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776683; hg19: chr5-177421298;