rs543698823
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_006017.3(PROM1):c.1354_1355insT(p.Tyr452LeufsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.000331 in 1,612,370 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (โ โ ). Synonymous variant affecting the same amino acid position (i.e. YY452F?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_006017.3 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROM1 | NM_006017.3 | c.1354_1355insT | p.Tyr452LeufsTer13 | frameshift_variant | 13/28 | ENST00000447510.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROM1 | ENST00000447510.7 | c.1354_1355insT | p.Tyr452LeufsTer13 | frameshift_variant | 13/28 | 1 | NM_006017.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000217 AC: 33AN: 151932Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000220 AC: 54AN: 245996Hom.: 0 AF XY: 0.000225 AC XY: 30AN XY: 133438
GnomAD4 exome AF: 0.000343 AC: 501AN: 1460438Hom.: 0 Cov.: 30 AF XY: 0.000381 AC XY: 277AN XY: 726338
GnomAD4 genome ? AF: 0.000217 AC: 33AN: 151932Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74180
ClinVar
Submissions by phenotype
Cone-rod dystrophy 12 Pathogenic:4
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The homozygous p.Tyr452LeufsTer13 variant in PROM1 was identified by our study in one individual with cone-rod dystrophy. The p.Tyr452LeufsTer13 variant in PROM1 has been previously reported in 7 unrelated individuals with PROM1-associated retinopathy (PMID: 28041643, PMID: 19718270, PMID: 24154662, PMID: 26103963, PMID: 27874104, PMID: 25999674) and segregated with disease in 3 affected relatives from one family (PMID: 19718270) but has been identified in 0.05% (8/15262) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs543698823). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 7 previously reported unrelated individuals with PROM1-associated retinopathy (PMID: 28041643, PMID: 19718270, PMID: 24154662, PMID: 26103963, PMID: 27874104, PMID: 25999674), 3 were homozygotes (PMID: 19718270, PMID: 26103963, PMID: 27874104) and 3 were compound heterozygotes who carried pathogenic or likely pathogenic variants with unknown phase (PMID: 28041643, ClinVar Variation ID: 236527; PMID: 24154662, ClinVar Variation ID: 438215; PMID: 26103963, NC_000004.12:g.16006536A>G), which increases the likelihood that the p.Tyr452LeufsTer13 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 372711) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the proteinโรรดs amino acid sequence beginning at position 452 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the PROM1 gene is an established disease mechanism in autosomal recessive PROM1-associated retinal disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive neuronal PROM1-associated retinal disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Nov 25, 2022 | This variant was identified as homozygous._x000D_ Criteria applied: PVS1, PM3, PP4 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Dec 14, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Retinitis pigmentosa 41 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The PROM1 c.1354dup variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-M. Based on this evidence we have classified this variant as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals | Feb 01, 2019 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2022 | Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19718270, 24154662, 27874104, 25472526) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Tyr452Leufs*13) in the PROM1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROM1 are known to be pathogenic (PMID: 17605048, 19718270, 24154662, 25474345). This variant is present in population databases (rs543698823, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cone-rod dystrophy, or retinal disease (PMID: 19718270, 24154662, 27874104, 28041643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372711). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | PROM1: PVS1, PM3:Strong, PM2, PP1:Moderate - |
Retinal dystrophy Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 05, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Sep 15, 2017 | - - |
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
PROM1-related disorder Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The PROM1 c.1354dupT (p.Tyr452LeufsTer13) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Tyr452LeufsTer13 variant has been reported in at least five studies in a total of six individuals with PROM1-related disorders, including two homozygotes and one presumed compound heterozygote with cone or cone-rod dystrophy, and in one homozygote, one presumed compound heterozygote, and one heterozygote with retinitis pigmentosa (Pras et al. 2009; Wang et al. 2014; van Huet et al. 2015; Boulanger-Scemama et al. 2015; Habibi et al. 2016). The p.Tyr452LeufsTer13 variant was absent from 100 controls and is reported with a frequency of 0.00026 in the European (non-Finnish) population from the Exome Aggregation Consortium. While some variants in the PROM1 gene have been associated with both autosomal dominant and autosomal recessive PROM1-related disorders, review of the available literature reveals that this variant appears to be contributing to an autosomal recessive mode of inheritance for cone/cone-rod dystrophy and retinitis pigmentosa. Based on the evidence and due to the potential impact of frameshift variants, the p.Tyr452LeufsTer13 is classified as likely pathogenic for PROM1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 13, 2023 | The PROM1 c.1354dupT variant is predicted to result in a frameshift and premature protein termination (p.Tyr452Leufs*13). This variant has been reported in the homozygous and compound heterozygous states in individuals with cone-rod dystrophy and retinitis pigmentosa (referred to as c.1349insT in Pras et al. 2009. PubMed ID: 19718270; referred to as c.1354_1355insT in Wang et al. 2014. PubMed ID: 24154662). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-16008260-T-TA). Frameshift variants in PROM1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Autosomal recessive retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Faculty of Health Sciences, Beirut Arab University | Nov 22, 2016 | - - |
Cone-rod dystrophy 2 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Genetics in Ophthalmology, Institut Imagine | - | - - |
Stargardt disease Pathogenic:1
Pathogenic, no assertion criteria provided | research | Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana | Dec 14, 2022 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at