VCV002856969.2 - ClinVar

NM_152443.3(RDH12):c.189del (p.Ala64fs)

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.

(2)

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_152443.3(RDH12):c.189del (p.Ala64fs)

Variation ID: 2856969 Accession: VCV002856969.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 14q24.1 14: 67725100 (GRCh38) [ NCBI UCSC ] 14: 68191817 (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 20, 2024	Mar 30, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_152443.3:c.189del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689656.2:p.Ala64fs	frameshift
NM_152443.3:c.189delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000014.9:g.67725100del
NC_000014.8:g.68191817del
NG_008321.1:g.28215del
NG_008875.2:g.1221955del

... more HGVS ... less HGVS

Protein change

A64fs

Other names

Canonical SPDI

NC_000014.9:67725099: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.

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.
GPHN		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	757	1928
RDH12		-	-	GRCh38 GRCh37	5	622

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.
Leber congenital amaurosis 13	Pathogenic (1)	criteria provided, single submitter	Oct 19, 2023	RCV003605005.2
Leber congenital amaurosis	Pathogenic (1)	criteria provided, single submitter	Jan 11, 2024	RCV003988140.1

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 (Oct 19, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 13 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004458741.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 17964524‚ 22065924‚ 32014858‚ 34001834‚ 36284670 Comment: This sequence change creates a premature translational stop signal (p.Ala64Profs11) in the RDH12 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ala64Profs11) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 36284670). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004804485.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 36284670 Comment: Variant summary: RDH12 c.189delA (p.Ala64ProfsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more) Variant summary: RDH12 c.189delA (p.Ala64ProfsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251488 control chromosomes (gnomAD). c.189delA has been reported in the literature in an individual affected with retinitis pigmentosa (Gupta_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36284670). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Comment:

This sequence change creates a premature translational stop signal (p.Ala64Profs*11) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924, 32014858, 34001834). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 36284670). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: RDH12 c.189delA (p.Ala64ProfsX11) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251488 control chromosomes (gnomAD). c.189delA has been reported in the literature in an individual affected with retinitis pigmentosa (Gupta_2022). The following publication has been ascertained in the context of this evaluation (PMID: 36284670). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.

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
Identification of numerous novel disease-causing variants in patients with inherited retinal diseases, combining careful clinical-functional phenotyping with systematic, broad NGS panel-based genotyping.	Gupta PR	Molecular vision	2022	PMID: 36284670
ISOLATED MACULOPATHY AND MODERATE ROD-CONE DYSTROPHY REPRESENT THE MILDER END OF THE RDH12-RELATED RETINAL DYSTROPHY SPECTRUM.	De Zaeytijd J	Retina (Philadelphia, Pa.)	2021	PMID: 34001834
Expanding the phenotypic spectrum in RDH12-associated retinal disease.	Scott HA	Cold Spring Harbor molecular case studies	2020	PMID: 32014858
RDH12 retinopathy: novel mutations and phenotypic description.	Mackay DS	Molecular vision	2011	PMID: 22065924
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.	Stone EM	American journal of ophthalmology	2007	PMID: 17964524

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_152443.3(RDH12):c.189del (p.Ala64fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...