VCV000005610.52 - ClinVar

NM_006017.3(PROM1):c.1117C>T (p.Arg373Cys)

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.

(19)

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_006017.3(PROM1):c.1117C>T (p.Arg373Cys)

Variation ID: 5610 Accession: VCV000005610.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p15.32 4: 16013299 (GRCh38) [ NCBI UCSC ] 4: 16014922 (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	Apr 4, 2013	Oct 20, 2024	Aug 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006017.3:c.1117C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006008.1:p.Arg373Cys	missense
NM_001145847.2:c.1090C>T	NP_001139319.1:p.Arg364Cys	missense
NM_001145848.2:c.1090C>T	NP_001139320.1:p.Arg364Cys	missense
NM_001145849.2:c.1117C>T	NP_001139321.1:p.Arg373Cys	missense
NM_001145850.2:c.1117C>T	NP_001139322.1:p.Arg373Cys	missense
NM_001145851.2:c.1090C>T	NP_001139323.1:p.Arg364Cys	missense
NM_001145852.2:c.1090C>T	NP_001139324.1:p.Arg364Cys	missense
NM_001371406.1:c.1090C>T	NP_001358335.1:p.Arg364Cys	missense
NM_001371407.1:c.1090C>T	NP_001358336.1:p.Arg364Cys	missense
NM_001371408.1:c.1090C>T	NP_001358337.1:p.Arg364Cys	missense
NC_000004.12:g.16013299G>A
NC_000004.11:g.16014922G>A
NG_011696.2:g.75761C>T
	O43490:p.Arg373Cys

... more HGVS ... less HGVS

Protein change

R373C, R364C

Other names

NP_006008.1:p.(Arg373Cys)

Canonical SPDI

NC_000004.12:16013298: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA117645 UniProtKB: O43490#VAR_057961 OMIM: 604365.0003 dbSNP: rs137853006 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.
PROM1		-	-	GRCh38 GRCh37	999	1056

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.
Stargardt disease 4	Pathogenic (1)	no assertion criteria provided	Sep 1, 2010	RCV000005960.6
Retinal macular dystrophy type 2	Pathogenic (2)	criteria provided, single submitter	Jul 24, 2023	RCV000005961.6
Cone-rod dystrophy 12	Pathogenic (1)	no assertion criteria provided	Sep 1, 2010	RCV000005962.6
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Aug 16, 2024	RCV000479499.44
Retinal dystrophy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV000504765.6
Stargardt disease	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787648.2
Cone-rod dystrophy 12 Retinal macular dystrophy type 2 Retinitis pigmentosa 41 Stargardt disease 4	Pathogenic (1)	criteria provided, single submitter	May 18, 2022	RCV002496275.3
Macular dystrophy	Pathogenic (1)	no assertion criteria provided	Apr 1, 2018	RCV000787649.2
Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2021	RCV001723543.6

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 (Nov 22, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000702412.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 15, 2018	Publications: PubMed (6) PubMed: 18654668‚ 20393116‚ 20859302‚ 22183351‚ 22581970‚ 25356976 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PROM1 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Jul 18, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241446.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762040.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Cone-rod dystrophy (present) Sex: male
Pathogenic (May 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Stargardt disease 4 Retinal macular dystrophy type 2 Retinitis pigmentosa 41 Cone-rod dystrophy 12 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813984.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004706464.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950331.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (13) PubMed: 34906470‚ 10205271‚ 12657606‚ 18654668‚ 20393116‚ 20859302‚ 22183351‚ 22581970‚ 25356976‚ 28041643‚ 28559085‚ 29847639‚ 30718709 Comment: The p.Arg373Cys variant in PROM1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Arg373Cys variant in PROM1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinal macular dystrophy type 2 Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030437.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PM2, PS4.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: female Geographic origin: Portugal
Pathogenic (Jan 29, 2024)	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: SCV001232460.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 18654668‚ 20393116‚ 22183351‚ 28559085‚ 29847639 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the PROM1 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the PROM1 protein (p.Arg373Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant forms of retinal dystrophy (PMID: 18654668, 20393116, 22183351, 28559085, 29847639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5610). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PROM1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROM1 function (PMID: 18654668). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568218.8 First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024	Comment: Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein … (more) Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein mislocalization (PMID: 18654668); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28840994, 29847639, 12657606, 23161075, 25356976, 26667666, 25133751, 28559085, 32531858, 31144483, 31129250, 10205271, 25590640, 27624628, 28076437, 27160483, 26103963, 20393116, 28041643, 23891399, 31054281, 32820593, 32534057, 31736247, 32581362, 34008001, 33090715, 30653986, 22581970, 22183351, 20859302, 29555955, 36259723, 38072963, 36460718, 31213501, 36729443, 36819107, 36909829, 33749171, 36284460, 37734845, 30926958, 18654668) (less)
Pathogenic (May 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250320.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PROM1: PP1:Strong, PS4, PM2, PP4, PS3:Supporting, BP4 Number of individuals with the variant: 4
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinal dystrophy Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000599170.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 18654668 Observation 1: Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: NA Observation 2: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Stargardt disease Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926637.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (Apr 01, 2018)	no assertion criteria provided Method: research	Macular dystrophy Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926638.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001972221.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Sep 01, 2010)	no assertion criteria provided Method: literature only	MACULAR DYSTROPHY, RETINAL, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026143.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 08, 2023	Publications: PubMed (8) PubMed: 10205271‚ 12657606‚ 18654668‚ 20393116‚ 9634506‚ 12659814‚ 15665353‚ 35947379 Comment on evidence: In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal … (more) In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal macular dystrophy-2 (MCDR2; 608051), previously reported by Michaelides et al. (2003), Yang et al. (2008) identified heterozygosity for a 1117C-T transition in exon 10 of the PROM1 gene, resulting in an arg373-to-cys (R373C) substitution. The authors also identified the R373C mutation in affected members of a family with cone-rod dystrophy (CORD12; 612657). Haplotype analysis indicated that the mutation had arisen independently in each of the 3 families, and it was not found in 400 matched controls. Studies in transgenic mice showed both mutant and endogenous PROM1 throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments where PROM1 is normally localized, and the outer segment disc membranes were greatly overgrown and misplaced, indicating defective disc morphogenesis. Michaelides et al. (2010) examined affected members of 5 families with the R373C mutation in the PROM1 gene, including 3 previously studied families (Kniazeva et al., 1999, Michaelides et al., 2003, and Yang et al., 2008, respectively) and 2 newly ascertained British families in which affected individuals had bull's eye macular dystrophy (families 'D' and 'E'). The authors observed that the R373C mutation produces an autosomal dominant, fully penetrant retinopathy characterized by the consistent finding of bull's-eye maculopathy, with variable rod or rod-cone dysfunction displaying marked intra- and interfamilial variability, and phenotypes ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction. Michaelides et al. (2010) noted that all reported patients with the R373C mutation exhibited only an ocular phenotype, despite ubiquitous expression of PROM1 in plasma membrane protrusions. In 9 affected members of a 4-generation British family with cone-rod dystrophy, originally described by Kelsell et al. (1998) and later restudied by Johnson et al. (2003) and Michaelides et al. (2005), Martin-Gutierrez et al. (2022) identified heterozygosity for the recurrent R373C substitution in the PROM1 gene. In addition, review of the Moorfields Eye Hospital patient database revealed 27 more patients with retinal dystrophy who were carriers of the R373C PROM1 variant. (less)
Pathogenic (Sep 01, 2010)	no assertion criteria provided Method: literature only	CONE-ROD DYSTROPHY 12 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026144.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 08, 2023	Publications: PubMed (8) PubMed: 10205271‚ 12657606‚ 18654668‚ 20393116‚ 9634506‚ 12659814‚ 15665353‚ 35947379 Comment on evidence: In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal … (more) In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal macular dystrophy-2 (MCDR2; 608051), previously reported by Michaelides et al. (2003), Yang et al. (2008) identified heterozygosity for a 1117C-T transition in exon 10 of the PROM1 gene, resulting in an arg373-to-cys (R373C) substitution. The authors also identified the R373C mutation in affected members of a family with cone-rod dystrophy (CORD12; 612657). Haplotype analysis indicated that the mutation had arisen independently in each of the 3 families, and it was not found in 400 matched controls. Studies in transgenic mice showed both mutant and endogenous PROM1 throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments where PROM1 is normally localized, and the outer segment disc membranes were greatly overgrown and misplaced, indicating defective disc morphogenesis. Michaelides et al. (2010) examined affected members of 5 families with the R373C mutation in the PROM1 gene, including 3 previously studied families (Kniazeva et al., 1999, Michaelides et al., 2003, and Yang et al., 2008, respectively) and 2 newly ascertained British families in which affected individuals had bull's eye macular dystrophy (families 'D' and 'E'). The authors observed that the R373C mutation produces an autosomal dominant, fully penetrant retinopathy characterized by the consistent finding of bull's-eye maculopathy, with variable rod or rod-cone dysfunction displaying marked intra- and interfamilial variability, and phenotypes ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction. Michaelides et al. (2010) noted that all reported patients with the R373C mutation exhibited only an ocular phenotype, despite ubiquitous expression of PROM1 in plasma membrane protrusions. In 9 affected members of a 4-generation British family with cone-rod dystrophy, originally described by Kelsell et al. (1998) and later restudied by Johnson et al. (2003) and Michaelides et al. (2005), Martin-Gutierrez et al. (2022) identified heterozygosity for the recurrent R373C substitution in the PROM1 gene. In addition, review of the Moorfields Eye Hospital patient database revealed 27 more patients with retinal dystrophy who were carriers of the R373C PROM1 variant. (less)
Pathogenic (Sep 01, 2010)	no assertion criteria provided Method: literature only	STARGARDT DISEASE 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026142.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 08, 2023	Publications: PubMed (8) PubMed: 10205271‚ 12657606‚ 18654668‚ 20393116‚ 9634506‚ 12659814‚ 15665353‚ 35947379 Comment on evidence: In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal … (more) In affected members of a family with a Stargardt-like phenotype (STGD4; 603786), previously described by Kniazeva et al. (1999), and an unrelated family with retinal macular dystrophy-2 (MCDR2; 608051), previously reported by Michaelides et al. (2003), Yang et al. (2008) identified heterozygosity for a 1117C-T transition in exon 10 of the PROM1 gene, resulting in an arg373-to-cys (R373C) substitution. The authors also identified the R373C mutation in affected members of a family with cone-rod dystrophy (CORD12; 612657). Haplotype analysis indicated that the mutation had arisen independently in each of the 3 families, and it was not found in 400 matched controls. Studies in transgenic mice showed both mutant and endogenous PROM1 throughout the layers of the photoreceptors, rather than at the base of the photoreceptor outer segments where PROM1 is normally localized, and the outer segment disc membranes were greatly overgrown and misplaced, indicating defective disc morphogenesis. Michaelides et al. (2010) examined affected members of 5 families with the R373C mutation in the PROM1 gene, including 3 previously studied families (Kniazeva et al., 1999, Michaelides et al., 2003, and Yang et al., 2008, respectively) and 2 newly ascertained British families in which affected individuals had bull's eye macular dystrophy (families 'D' and 'E'). The authors observed that the R373C mutation produces an autosomal dominant, fully penetrant retinopathy characterized by the consistent finding of bull's-eye maculopathy, with variable rod or rod-cone dysfunction displaying marked intra- and interfamilial variability, and phenotypes ranging from isolated maculopathy without generalized photoreceptor dysfunction to maculopathy associated with very severe rod-cone dysfunction. Michaelides et al. (2010) noted that all reported patients with the R373C mutation exhibited only an ocular phenotype, despite ubiquitous expression of PROM1 in plasma membrane protrusions. In 9 affected members of a 4-generation British family with cone-rod dystrophy, originally described by Kelsell et al. (1998) and later restudied by Johnson et al. (2003) and Michaelides et al. (2005), Martin-Gutierrez et al. (2022) identified heterozygosity for the recurrent R373C substitution in the PROM1 gene. In addition, review of the Moorfields Eye Hospital patient database revealed 27 more patients with retinal dystrophy who were carriers of the R373C PROM1 variant. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001921006.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958689.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
click to load more click to collapse

Comment:

The p.Arg373Cys variant in PROM1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PS3, PP1-S. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the PROM1 protein (p.Arg373Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal dominant forms of retinal dystrophy (PMID: 18654668, 20393116, 22183351, 28559085, 29847639). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5610). 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) performed at Invitae indicates that this missense variant is not expected to disrupt PROM1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROM1 function (PMID: 18654668). For these reasons, this variant has been classified as Pathogenic.

Comment:

Transgenic mice carrying the R373C variant show progressive retinal abnormalities, and functional studies demonstrate a damaging effect with reduced actin binding as well as protein mislocalization (PMID: 18654668); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28840994, 29847639, 12657606, 23161075, 25356976, 26667666, 25133751, 28559085, 32531858, 31144483, 31129250, 10205271, 25590640, 27624628, 28076437, 27160483, 26103963, 20393116, 28041643, 23891399, 31054281, 32820593, 32534057, 31736247, 32581362, 34008001, 33090715, 30653986, 22581970, 22183351, 20859302, 29555955, 36259723, 38072963, 36460718, 31213501, 36729443, 36819107, 36909829, 33749171, 36284460, 37734845, 30926958, 18654668)

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
The first genetic landscape of inherited retinal dystrophies in Portuguese patients identifies recurrent homozygous mutations as a frequent cause of pathogenesis.	Peter VG	PNAS nexus	2023	PMID: 36909829
Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1.	Martin-Gutierrez MP	Investigative ophthalmology & visual science	2022	PMID: 35947379
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Toward the Mutational Landscape of Autosomal Dominant Retinitis Pigmentosa: A Comprehensive Analysis of 258 Spanish Families.	Martin-Merida I	Investigative ophthalmology & visual science	2018	PMID: 29847639
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing.	Huang XF	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356976
A paradigm shift in the delivery of services for diagnosis of inherited retinal disease.	O'Sullivan J	Journal of medical genetics	2012	PMID: 22581970
Genes and mutations in autosomal dominant cone and cone-rod dystrophy.	Kohl S	Advances in experimental medicine and biology	2012	PMID: 22183351
Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy.	Arrigoni FI	European journal of human genetics : EJHG	2011	PMID: 20859302
The PROM1 mutation p.R373C causes an autosomal dominant bull's eye maculopathy associated with rod, rod-cone, and macular dystrophy.	Michaelides M	Investigative ophthalmology & visual science	2010	PMID: 20393116
Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice.	Yang Z	The Journal of clinical investigation	2008	PMID: 18654668
A detailed study of the phenotype of an autosomal dominant cone-rod dystrophy (CORD7) associated with mutation in the gene for RIM1.	Michaelides M	The British journal of ophthalmology	2005	PMID: 15665353
Genomic organisation and alternative splicing of human RIM1, a gene implicated in autosomal dominant cone-rod dystrophy (CORD7).	Johnson S	Genomics	2003	PMID: 12659814
An autosomal dominant bull's-eye macular dystrophy (MCDR2) that maps to the short arm of chromosome 4.	Michaelides M	Investigative ophthalmology & visual science	2003	PMID: 12657606
A new locus for autosomal dominant stargardt-like disease maps to chromosome 4.	Kniazeva M	American journal of human genetics	1999	PMID: 10205271
Localization of a gene (CORD7) for a dominant cone-rod dystrophy to chromosome 6q.	Kelsell RE	American journal of human genetics	1998	PMID: 9634506
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PROM1	-	-	-	-
click to load more click to collapse

Text-mined citations for rs137853006 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_006017.3(PROM1):c.1117C>T (p.Arg373Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853006 ...