VCV001240018.7 - ClinVar

NM_001563.4(IMPG1):c.1824+1G>A

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.

(5)

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/Likely 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_001563.4(IMPG1):c.1824+1G>A

Variation ID: 1240018 Accession: VCV001240018.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q14.1 6: 75950561 (GRCh38) [ NCBI UCSC ] 6: 76660278 (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	Sep 12, 2021	Feb 14, 2024	Jul 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001563.4:c.1824+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001282368.2:c.1590+1G>A		splice donor
NC_000006.12:g.75950561C>T
NC_000006.11:g.76660278C>T
NG_041812.1:g.127118G>A

... more HGVS ... less HGVS

Protein change

Other names

NP_001554.2:p.?
IVS23DS, G-A, +1

Canonical SPDI

NC_000006.12:75950560:C:T

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

OMIM: 602870.0007 dbSNP: rs770887047 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.
IMPG1		-	-	GRCh38 GRCh37	665	691

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.
Vitelliform macular dystrophy 4	Pathogenic (1)	no assertion criteria provided	Sep 10, 2021	RCV001637980.2
Benign concentric annular macular dystrophy	Likely pathogenic (2)	criteria provided, single submitter	Dec 9, 2021	RCV001637979.3
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 27, 2023	RCV002538519.3
Retinitis pigmentosa	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324567.2

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.
Likely pathogenic (Dec 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Benign concentric annular macular dystrophy Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002044433.1 First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022	Comment: _x000D_ Criteria applied: PVS1, PS4_SUP
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030415.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PVS1, PM2, PP5.	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 (Jun 27, 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: SCV003439499.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 23993198‚ 32817297‚ 16199547 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1240018). Disruption of this splice site has been observed in individuals with autosomal dominant retinitis pigmentosa and/or vitelliform macular dystrophy (PMID: 23993198, 32817297). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs770887047, gnomAD 0.003%). This sequence change affects a donor splice site in intron 13 of the IMPG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in IMPG1 cause disease. (less)
Pathogenic (Sep 10, 2021)	no assertion criteria provided Method: literature only	MACULAR DYSTROPHY, VITELLIFORM, 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001852752.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021	Publications: PubMed (1) PubMed: 32817297 Comment on evidence: Retinitis Pigmentosa 91 In affected members of a large 4-generation French family (family A) and a 49-year-old Spanish woman (family C) with retinitis pigmentosa (RP91; … (more) Retinitis Pigmentosa 91 In affected members of a large 4-generation French family (family A) and a 49-year-old Spanish woman (family C) with retinitis pigmentosa (RP91; 153870), Olivier et al. (2021) identified heterozygosity for a splicing mutation (c.1824+1G-A, NM_001563) in intron 13 of the IMPG1 gene. The mutation segregated fully with disease in the French family, being present in 6 affected individuals who had RP ranging in severity from mild to severe, as well as in 4 asymptomatic carriers in the youngest generation designated as 'preclinical,' who had grossly normal fundus examinations but showed abnormalities on imaging studies. The variant was also detected in the Spanish proband's asymptomatic 70-year-old mother, who had hard drusen-like deposits in the macula on funduscopy but did not undergo other ocular imaging. The variant was reported at low minor allele frequency in the gnomAD database (1/241,072). Vitelliform Macular Dystrophy 4 In a 47-year-old French woman (family B) with vitelliform macular dystrophy (VMD4; 616151), Olivier et al. (2021) identified heterozygosity for the c.1824+1G-A splicing mutation in the IMPG1 gene. The proband had reduced visual acuity with the typical vitelliform lesions seen on funduscopy; ocular coherence tomography revealed a hyperreflective deposit on the right and inactive choroidal neovascularization on the left, and electroretinography showed preserved rod and cone responses with a normal Arden ratio on electrooculogram. Her 2 sisters, aged 45 and 50 years, were asymptomatic carriers of the variant and had normal funduscopic examinations; other ocular studies were not reported. Their 70-year-old mother with 'low vision' also carried the variant; no other clinical details were available. (less)
Pathogenic (Sep 10, 2021)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 91 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001852751.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021	Publications: PubMed (1) PubMed: 32817297 Comment on evidence: Retinitis Pigmentosa 91 In affected members of a large 4-generation French family (family A) and a 49-year-old Spanish woman (family C) with retinitis pigmentosa (RP91; … (more) Retinitis Pigmentosa 91 In affected members of a large 4-generation French family (family A) and a 49-year-old Spanish woman (family C) with retinitis pigmentosa (RP91; 153870), Olivier et al. (2021) identified heterozygosity for a splicing mutation (c.1824+1G-A, NM_001563) in intron 13 of the IMPG1 gene. The mutation segregated fully with disease in the French family, being present in 6 affected individuals who had RP ranging in severity from mild to severe, as well as in 4 asymptomatic carriers in the youngest generation designated as 'preclinical,' who had grossly normal fundus examinations but showed abnormalities on imaging studies. The variant was also detected in the Spanish proband's asymptomatic 70-year-old mother, who had hard drusen-like deposits in the macula on funduscopy but did not undergo other ocular imaging. The variant was reported at low minor allele frequency in the gnomAD database (1/241,072). Vitelliform Macular Dystrophy 4 In a 47-year-old French woman (family B) with vitelliform macular dystrophy (VMD4; 616151), Olivier et al. (2021) identified heterozygosity for the c.1824+1G-A splicing mutation in the IMPG1 gene. The proband had reduced visual acuity with the typical vitelliform lesions seen on funduscopy; ocular coherence tomography revealed a hyperreflective deposit on the right and inactive choroidal neovascularization on the left, and electroretinography showed preserved rod and cone responses with a normal Arden ratio on electrooculogram. Her 2 sisters, aged 45 and 50 years, were asymptomatic carriers of the variant and had normal funduscopic examinations; other ocular studies were not reported. Their 70-year-old mother with 'low vision' also carried the variant; no other clinical details were available. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1240018). Disruption of this splice site has been observed in individuals with autosomal dominant retinitis pigmentosa and/or vitelliform macular dystrophy (PMID: 23993198, 32817297). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs770887047, gnomAD 0.003%). This sequence change affects a donor splice site in intron 13 of the IMPG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), however the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in IMPG1 cause disease.

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
Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa.	Olivier G	Journal of medical genetics	2021	PMID: 32817297
Mutations in IMPG1 cause vitelliform macular dystrophies.	Manes G	American journal of human genetics	2013	PMID: 23993198
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs770887047 ...

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_001563.4(IMPG1):c.1824+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770887047 ...