VCV002746009.1 - ClinVar

NM_006445.4(PRPF8):c.6956_6957dup (p.Leu2320fs)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006445.4(PRPF8):c.6956_6957dup (p.Leu2320fs)

Variation ID: 2746009 Accession: VCV002746009.1

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 17p13.3 17: 1650852-1650853 (GRCh38) [ NCBI UCSC ] 17: 1554146-1554147 (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	Feb 14, 2024	Feb 14, 2024	Jul 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006445.4:c.6956_6957dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006436.3:p.Leu2320fs	frameshift
NC_000017.11:g.1650854AG[3]
NC_000017.10:g.1554148AG[3]
NG_009118.1:g.39027TC[3]
NG_033061.1:g.4243TC[3]

... more HGVS ... less HGVS

Protein change

L2320fs

Other names

Canonical SPDI

NC_000017.11:1650852:GAGAG:GAGAGAG

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.

Links

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.
PRPF8		-	-	GRCh38 GRCh38 GRCh37	1368	1464

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 (1)	criteria provided, single submitter	Jul 24, 2023	RCV003568324.2

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 (Jul 24, 2023)	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: SCV004306562.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 20232351‚ 21378395‚ 28515276 Comment: For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRPF8 protein in which other variant(s) (p.Tyr2334Asn) have … (more) For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRPF8 protein in which other variant(s) (p.Tyr2334Asn) have been determined to be pathogenic (PMID: 20232351, 21378395, 28515276; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with PRPF8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the PRPF8 gene (p.Leu2320Serfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the PRPF8 protein and extend the protein by 23 additional amino acid residues. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PRPF8 protein in which other variant(s) (p.Tyr2334Asn) have been determined to be pathogenic (PMID: 20232351, 21378395, 28515276; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with PRPF8-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the PRPF8 gene (p.Leu2320Serfs*40). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the PRPF8 protein and extend the protein by 23 additional amino acid residues.

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
Assembly of the U5 snRNP component PRPF8 is controlled by the HSP90/R2TP chaperones.	Malinová A	The Journal of cell biology	2017	PMID: 28515276
PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa.	Tanackovic G	Human molecular genetics	2011	PMID: 21378395
Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes.	Towns KV	Human mutation	2010	PMID: 20232351

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_006445.4(PRPF8):c.6956_6957dup (p.Leu2320fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...