rs193922688

Positions:

• chr5-177994145-ACT-A

Variant summary

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

The ENST00000308304.2(PROP1):​c.301_302del​(p.Leu102CysfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,613,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S101S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PROP1 ENST00000308304.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:2
• Conservation: PhyloP100: 3.32

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. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177994145-ACT-A is Pathogenic according to our data. Variant chr5-177994145-ACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROP1	NM_006261.5	c.301_302del	p.Leu102CysfsTer8	frameshift_variant	2/3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.301_302del	p.Leu102CysfsTer8	frameshift_variant	2/3	1	NM_006261.5	ENSP00000311290	P1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151820 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251252 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461874 Hom.: 0 AF XY: 0.000208 AC XY: 151 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000235

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151820 Hom.: 0 Cov.: 31 AF XY: 0.0000944 AC XY: 7 AN XY: 74154

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000400 Hom.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Pathogenic:11 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 13, 2017	The PROP1 c.301_302delAG (p.Leu102CysfsTer8) variant results in a frameshift and is predicted to result in premature termination of the protein and loss of the DNA-binding homeodomain and C-terminal transactivation domain (Wu et al. 1998). Across a selection of the available literature, the p.Leu102CysfsTer8 variant has been reported in a total of 280 individuals with combined pituitary hormone deficiency, including 213 homozygotes, 64 compound heterozygotes, and three heterozygotes in whom a second variant was not been identified (Wu et al. 1998; Cogan et al. 1998; Fofanova et al. 1998; Deladoey et al. 1999; Mendonca et al. 1999; Pernasetti et al. 2000; Riepe et al. 2001; Lee et al. 2004; Avbelj Stefanija et al. 2015; Lazea et al. 2015; Dusatkova et al. 2016). The p.Leu102CysfsTer8 variant was shown to segregate with disease in a four-generation family (Pernasetti et al. 2000). The variant was absent from 193 controls but is reported at a frequency of 0.00109 in the European American population of the Exome Sequencing Project. Based on the collective evidence and the potential impact of frameshift variants, the p.Leu102CysfsTer8 variant is classified as pathogenic for combined pituitary hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_006261.4(PROP1):c.301_302delAG(aka L102Cfs*8) is classified as pathogenic in the context of combined pituitary hormone deficiency, PROP1 related. Sources cited for classification include the following: PMID 9462743 and 15126542. Classification of NM_006261.4(PROP1):c.301_302delAG(aka L102Cfs*8) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 20, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Jun 02, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 08, 2020	This variant was identified as compound heterozygous with NM_006261.4:c.358C>T. -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 04, 2022	This sequence variant is a two nucleotide deletion (delAG) at position c.301_302 of the coding sequence in exon 2 of 3 in the PROP1 gene. The c.301_302del allele has multiple desigtions and may be referred to as A301G302, 296delAG, or GA296 in the literature. This deletion results a premature termition sigl 8 codons downstream of the frameshift introduced at codon 102. While this variant is not expected to undergo nonsense mediated decay, a premature termition at this position would elimite the PROP1 protein's D binding and transcriptiol activation domains which are crucial to this protein's role in regulating the growth of the pituitary gland (PMID: 15591534). This is a previously reported variant (ClinVar) and is one of the most common variants associated with combined pituitary hormone deficiency (PMID: 31090814, 27828722). This variant has been observed in both the homozygous and compound heterozygous states in numerous individuals with combined pituitary hormone deficiency (PMID: 9745452, 11081182, 10084575, 10323394, 9462743) and has been observed to co-segregate with combined pituitary hormone deficiency in multiple individuals across a six-generation pedigree (PMID: 10634415). This variant is observed in control population datasets (gnomAD database, 51 of 282,522 alleles, 0.02%). A functiol alysis of the protein generated by this variant has confirmed that D binding and transactivation is significantly reduced by the variant relative to the wildtype protein (PMID: 9462743). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM3, PP1, PS3, PVS1 -
not provided, no classification provided	literature only	GeneReviews	-	Common variant in Europe & Latin America [Dusatkova et al 2016]; founder variant in Lithuania [Navardauskaite et al 2014] & Hutterite population [Wu et al 1998]; Impaired gonadotropic function occurs in all individuals with the most common PROP1 variant, c.301_302delAG [Madeira et al 2017]. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Likely pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2024	Frameshift variant predicted to result in abnormal protein length as the last 125 amino acids are replaced with 7 different amino acids, and other similar variants have been reported in HGMD; Published functional studies demonstrate a damaging effect on DNA binding and transactivation function (PMID: 9462743); This variant is associated with the following publications: (PMID: 28734020, 12414875, 16984240, 17526936, 15472175, 10084575, 25581745, 30959475, 31948187, 31090814, 31093944, 32415500, 33098107, 11081182, 26111865, 10323394, 15126542, 10634415, 26059845, 17162714, 16735499, 16703408, 18157385, 11022176, 9462743, 11549674, 30266296, 34426522, 31589614, 32612575, 9745452) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Leu102Cysfs*8) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs193922688, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with combined pituitary hormone deficiency in many families and it has been observed in combination with another PROP1 variant in unrelated individuals with this condition (PMID: 9462743, 11081182, 16735499, 17162714, 26111865, 28734020). It has also been observed to segregate with disease in related individuals. This variant is also known as A301G302 deletion and delGA296 (S109X). ClinVar contains an entry for this variant (Variation ID: 8098). 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: 9462743). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 04, 2023	- -

46,XY partial gonadal dysgenesis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Aug 01, 2020

- -

PROP1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2024

The PROP1 c.301_302delAG variant is predicted to result in a frameshift and premature protein termination (p.Leu102Cysfs*8). This variant in the homozygous or compound heterozygous state has been reported in individuals with combined pituitary hormone deficiency in many families (see example: Wu et al. 1998. PubMed ID: 9462743; Avbelj Stefanija et al. 2015. PubMed ID: 26111865; Blum et al. 2018. PubMed ID: 30266296). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in PROP1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Combined pituitary hormone deficiencies, genetic form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: -39

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922688; hg19: chr5-177421146;