VCV000488802.13 - ClinVar

NM_152443.3(RDH12):c.250C>T (p.Arg84Ter)

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_152443.3(RDH12):c.250C>T (p.Arg84Ter)

Variation ID: 488802 Accession: VCV000488802.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q24.1 14: 67725161 (GRCh38) [ NCBI UCSC ] 14: 68191878 (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 13, 2018	Jun 17, 2024	Dec 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_152443.3:c.250C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_689656.2:p.Arg84Ter	nonsense
NC_000014.9:g.67725161C>T
NC_000014.8:g.68191878C>T
NG_008321.1:g.28276C>T

Protein change

R84*

Other names

Canonical SPDI

NC_000014.9:67725160:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

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

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA390148606 dbSNP: rs1349849938 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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 28, 2017	RCV000578516.8
Leber congenital amaurosis 13	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 2, 2023	RCV001058196.18

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 (Nov 28, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680684.1 First in ClinVar: Feb 13, 2018 Last updated: Feb 13, 2018	Comment: The R84X variant in the RDH12 gene has been reported previously in association with autosomal recessive early onset retinal dystrophy (Mackay et al., 2011). This … (more) The R84X variant in the RDH12 gene has been reported previously in association with autosomal recessive early onset retinal dystrophy (Mackay et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R84X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R84X as a likely pathogenic variant. (less)
Pathogenic (Aug 24, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Leber congenital amaurosis 13 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breda Genetics srl Accession: SCV001443679.1 First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020	Publications: PubMed (1) PubMed: 22065924 Comment: The variant c.250C>T (p.Arg84) in the RDH12 gene is reported as pathogenic/likely pathogenic for Leber congenital amaurosis 13 in ClinVar (Variation ID: 488802). The variant … (more) The variant c.250C>T (p.Arg84) in the RDH12 gene is reported as pathogenic/likely pathogenic for Leber congenital amaurosis 13 in ClinVar (Variation ID: 488802). The variant creates a premature stop codon at amino acid position Arg84, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.000003976 in gnomAD exomes, with no homozygous individuals reported. The pathogenic variant c.250C>T (p.Arg84*) has been reported by Mackay et al. (2011) in a patient with nonsyndromic autosomal recessive retinal dystrophy (PMID: 22065924). (less)
Pathogenic (Oct 29, 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: SCV001222747.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (4) PubMed: 17964524‚ 22065924‚ 32014858‚ 34001834 Comment: This sequence change creates a premature translational stop signal (p.Arg84) 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.Arg84) 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 present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 22065924). ClinVar contains an entry for this variant (Variation ID: 488802). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Dec 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 13 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208593.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	no assertion criteria provided Method: research	Leber congenital amaurosis 13 Affected status: yes Allele origin: inherited	Laboratory of Genetics in Ophthalmology, Institut Imagine Accession: SCV001432270.1 First in ClinVar: Sep 16, 2020 Last updated: Sep 16, 2020	Publications: PubMed (1) PubMed: 22065924 Number of individuals with the variant: 1

Comment:

The R84X variant in the RDH12 gene has been reported previously in association with autosomal recessive early onset retinal dystrophy (Mackay et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R84X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R84X as a likely pathogenic variant.

Comment:

The variant c.250C>T (p.Arg84*) in the RDH12 gene is reported as pathogenic/likely pathogenic for Leber congenital amaurosis 13 in ClinVar (Variation ID: 488802). The variant creates a premature stop codon at amino acid position Arg84, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.000003976 in gnomAD exomes, with no homozygous individuals reported. The pathogenic variant c.250C>T (p.Arg84*) has been reported by Mackay et al. (2011) in a patient with nonsyndromic autosomal recessive retinal dystrophy (PMID: 22065924).

Comment:

This sequence change creates a premature translational stop signal (p.Arg84*) 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 present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Leber congenital amaurosis (PMID: 22065924). ClinVar contains an entry for this variant (Variation ID: 488802). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
loss_of_function_variant (SO:0002054)			Breda Genetics srl Accession: SCV001443679.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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 rs1349849938 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_152443.3(RDH12):c.250C>T (p.Arg84Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1349849938 ...