VCV000620129.12 - ClinVar

NM_006269.2(RP1):c.1625C>G (p.Ser542Ter)

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.

(4)

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_006269.2(RP1):c.1625C>G (p.Ser542Ter)

Variation ID: 620129 Accession: VCV000620129.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q12.1 8: 54625507 (GRCh38) [ NCBI UCSC ] 8: 55538067 (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	Mar 19, 2019	Sep 16, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006269.2:c.1625C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006260.1:p.Ser542Ter	nonsense
NC_000008.11:g.54625507C>G
NC_000008.10:g.55538067C>G
NG_009840.2:g.14441C>G

Protein change

S542*

Other names

Canonical SPDI

NC_000008.11:54625506:C:G

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00005

Links

dbSNP: rs779334655 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.
RP1		-	-	GRCh38 GRCh37	1277	1541

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.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV000760408.10
Retinitis pigmentosa	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 1, 2021	RCV000988060.4

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 (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Retinitis pigmentosa Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137625.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950350.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (6) PubMed: 34906470‚ 22917891‚ 25097241‚ 25692139‚ 30337596‚ 29912909 Comment: The p.Ser542Ter variant in RP1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Ser542Ter variant in RP1 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: PVS1, PM2, PS4. 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 (Jan 11, 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: SCV001210261.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 22917891‚ 25097241‚ 25692139‚ 30337596‚ 11527933‚ 19933189‚ 29425069‚ 30027431‚ 33681214 Comment: This sequence change creates a premature translational stop signal (p.Ser542) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, … (more) This sequence change creates a premature translational stop signal (p.Ser542) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1615 amino acid(s) of the RP1 protein. This variant is present in population databases (rs779334655, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 22917891, 25097241, 25692139, 30337596). ClinVar contains an entry for this variant (Variation ID: 620129). This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431, 33681214). Therefore, variants that disrupt this region are expected to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 29, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000890284.2 First in ClinVar: Mar 19, 2019 Last updated: Sep 16, 2024	Comment: Nonsense variant predicted to result in protein truncation, as the last 1615 amino acids are lost, and other loss-of-function variants have been reported downstream in … (more) Nonsense variant predicted to result in protein truncation, as the last 1615 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32483926, 32531858, 22917891, 25097241, 27353947, 25692139, 28157192, 29912909, 30337596, 31589614, 32005865, 36341727, 36819107, 33452396, 34906470) (less)

Comment:

The p.Ser542Ter variant in RP1 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: PVS1, PM2, PS4. 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 creates a premature translational stop signal (p.Ser542*) in the RP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1615 amino acid(s) of the RP1 protein. This variant is present in population databases (rs779334655, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive retinal dystrophy (PMID: 22917891, 25097241, 25692139, 30337596). ClinVar contains an entry for this variant (Variation ID: 620129). This variant disrupts the C-terminus of the RP1 protein. Many variants that disrupt this region have been reported in individuals with either autosomal dominant or autosomal recessive retinitis pigmentosa (PMID: 11527933, 19933189, 29425069, 30027431, 33681214). Therefore, variants that disrupt this region are expected to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation, as the last 1615 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 32483926, 32531858, 22917891, 25097241, 27353947, 25692139, 28157192, 29912909, 30337596, 31589614, 32005865, 36341727, 36819107, 33452396, 34906470)

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 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
Dominant RP in the Middle While Recessive in Both the N- and C-Terminals Due to RP1 Truncations: Confirmation, Refinement, and Questions.	Wang J	Frontiers in cell and developmental biology	2021	PMID: 33681214
A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.	Ezquerra-Inchausti M	Scientific reports	2018	PMID: 30337596
Clinical and genetic findings of a Japanese patient with RP1-related autosomal recessive retinitis pigmentosa.	Kurata K	Documenta ophthalmologica. Advances in ophthalmology	2018	PMID: 30027431
Unravelling the pathogenic role and genotype-phenotype correlation of the USH2A p.(Cys759Phe) variant among Spanish families.	Pérez-Carro R	PloS one	2018	PMID: 29912909
Targeted Next-Generation Sequencing Reveals Novel RP1 Mutations in Autosomal Recessive Retinitis Pigmentosa.	Li S	Genetic testing and molecular biomarkers	2018	PMID: 29425069
Targeted next generation sequencing identifies novel mutations in RP1 as a relatively common cause of autosomal recessive rod-cone dystrophy.	El Shamieh S	BioMed research international	2015	PMID: 25692139
Dependable and efficient clinical utility of target capture-based deep sequencing in molecular diagnosis of retinitis pigmentosa.	Wang J	Investigative ophthalmology & visual science	2014	PMID: 25097241
Identification of an RP1 prevalent founder mutation and related phenotype in Spanish patients with early-onset autosomal recessive retinitis.	Avila-Fernandez A	Ophthalmology	2012	PMID: 22917891
Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa.	Chen LJ	Investigative ophthalmology & visual science	2010	PMID: 19933189
Clinical features and mutations in patients with dominant retinitis pigmentosa-1 (RP1).	Berson EL	Investigative ophthalmology & visual science	2001	PMID: 11527933
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Text-mined citations for rs779334655 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_006269.2(RP1):c.1625C>G (p.Ser542Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779334655 ...