rs193922688

Variant names:

• chr5-177994145-ACT-A
• rs193922688
• NM_006261.5:c.301_302delAG

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.301_302delAG​(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PROP1 NM_006261.5 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. Fraction of 0.558 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 5-177994145-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 rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.301_302delAG	p.Leu102CysfsTer8	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.301_302delAG	p.Leu102CysfsTer8	frameshift_variant	Exon 2 of 3	1	NM_006261.5	ENSP00000311290.2

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

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 13, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 08, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous with NM_006261.4:c.358C>T. -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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/. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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]. -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 04, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Pathogenic:5

Aug 28, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2024

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.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 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: 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. -

Aug 11, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Dec 11, 2012

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

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

- -

46,XY partial gonadal dysgenesis Pathogenic:1

Aug 01, 2020

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Combined pituitary hormone deficiencies, genetic form Pathogenic:1

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

PROP1-related disorder Pathogenic:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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;