VCV000008003.51 - ClinVar

NM_002905.5(RDH5):c.712G>T (p.Gly238Trp)

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.

(13)

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_002905.5(RDH5):c.712G>T (p.Gly238Trp)

Variation ID: 8003 Accession: VCV000008003.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q13.2 12: 55724028 (GRCh38) [ NCBI UCSC ] 12: 56117812 (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	Apr 4, 2013	Oct 20, 2024	May 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002905.5:c.712G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002896.2:p.Gly238Trp	missense
NM_001199771.3:c.712G>T	NP_001186700.1:p.Gly238Trp	missense
NR_037658.1:n.771G>T		non-coding transcript variant
NC_000012.12:g.55724028G>T
NC_000012.11:g.56117812G>T
NG_008347.1:g.10099C>A
NG_008606.1:g.8662G>T
	Q92781:p.Gly238Trp

... more HGVS ... less HGVS

Protein change

G238W

Other names

NP_002896.2:p.(Gly238Trp)

Canonical SPDI

NC_000012.12:55724027:G: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.

0.00040 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00018

Trans-Omics for Precision Medicine (TOPMed) 0.00025

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Links

ClinGen: CA119196 UniProtKB: Q92781#VAR_009274 OMIM: 601617.0001 dbSNP: rs62638191 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.
BLOC1S1-RDH5	-	-	-	GRCh38	-	290
CD63		-	-	GRCh38 GRCh37	10	139
RDH5		-	-	GRCh38 GRCh37	-	283

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.
Fundus albipunctatus, autosomal recessive	Pathogenic (1)	no assertion criteria provided	Dec 30, 1999	RCV000008467.5
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 1, 2023	RCV000597673.35
Pigmentary retinal dystrophy	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 2, 2024	RCV000988861.9
See cases	Likely pathogenic (1)	criteria provided, single submitter	Jul 15, 2020	RCV002251890.3
RDH5-related disorder	Pathogenic (1)	no assertion criteria provided	Jun 29, 2024	RCV003390658.6
Congenital stationary night blindness	Pathogenic (1)	criteria provided, single submitter	Jul 24, 2023	RCV003324486.3

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 (Nov 29, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703236.2 First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018	Publications: PubMed (6) PubMed: 10369264‚ 10617778‚ 17476461‚ 18949499‚ 20829743‚ 21529959 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RDH5 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Pigmentary retinal dystrophy Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138753.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmentary retinal dystrophy Affected status: yes Allele origin: germline	3billion Accession: SCV002521584.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (3) PubMed: 10369264‚ 11675386‚ 10617778 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Functional studies provide strong evidence of the … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:11675386). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008003). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:10369264, 10617778). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Retinal dystrophy (present)
Pathogenic (Sep 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmentary retinal dystrophy Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019654.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 02, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pigmentary retinal dystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV005045622.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024
Pathogenic (Dec 18, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001810882.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: Published functional studies demonstrate a damaging effect; variant causes reduced enzymatic activity and different staining pattern with a strong perinuclear localization for G238W mutant cells … (more) Published functional studies demonstrate a damaging effect; variant causes reduced enzymatic activity and different staining pattern with a strong perinuclear localization for G238W mutant cells compared to wild type (Liden et al., 2001; Yamamoto et al., 1999); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31456290, 32141364, 17476461, 20829743, 10617778, 18949499, 10369264, 11675386) (less)
Likely pathogenic (Jul 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002523743.1 First in ClinVar: Jun 09, 2022 Last updated: Jun 09, 2022	Comment: ACMG classification criteria: PS3, PS4, PM2, PP1 Clinical Features: Neurodevelopmental abnormality (present) , Hypotonia (present) , Low-set ears (present) , Abnormality of vision (present) , Abnormality of coagulation (present) Geographic origin: Brazil
Pathogenic (Jul 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Congenital stationary night blindness Affected status: yes Allele origin: germline	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel Accession: SCV004030288.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023 Comment: This variant was classified as Pathogenic based on ACMG criteria: PP5, PP3, PM2.	Publications: PubMed (1) PubMed: 36909829 Comment: Clinical significance based on ACMG v2.0 Number of individuals with the variant: 1 Sex: male Geographic origin: Portugal
Pathogenic (Dec 01, 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: SCV001201296.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10369264‚ 10617778‚ 11675386 Comment: This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 238 of the RDH5 protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 238 of the RDH5 protein (p.Gly238Trp). This variant is present in population databases (rs62638191, gnomAD 0.05%). This missense change has been observed in individuals with fundus albipunctatus (PMID: 10369264, 10617778). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8003). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RDH5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RDH5 function (PMID: 11675386). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 01, 2017)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249019.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Dec 30, 1999)	no assertion criteria provided Method: literature only	FUNDUS ALBIPUNCTATUS, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028675.3 First in ClinVar: Apr 04, 2013 Last updated: May 26, 2024	Publications: PubMed (2) PubMed: 10369264‚ 10617778 Comment on evidence: In a patient with fundus albipunctatus (136880), Yamamoto et al. (1999) found homozygosity for a missense change: GGG (gly) to TGG (trp) in codon 238 … (more) In a patient with fundus albipunctatus (136880), Yamamoto et al. (1999) found homozygosity for a missense change: GGG (gly) to TGG (trp) in codon 238 of the RDH5 gene. In a second patient in an unrelated family, they found compound heterozygosity for the same gly238-to-trp (G238W) mutation and a ser73-to-phe (TCC to TTC) substitution (601617.0002). Gonzalez-Fernandez et al. (1999) identified homozygosity for the G238W mutation in 2 sibs with fundus albipunctatus. (less)
Pathogenic (Jun 29, 2024)	no assertion criteria provided Method: clinical testing	RDH5-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004110451.2 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The RDH5 c.712G>T variant is predicted to result in the amino acid substitution p.Gly238Trp. This variant has been reported in the homozygous and compound heterozygous … (more) The RDH5 c.712G>T variant is predicted to result in the amino acid substitution p.Gly238Trp. This variant has been reported in the homozygous and compound heterozygous states in individuals with autosomal recessive fundus albipunctatus (Yamamoto et al. 1999. PubMed ID: 10369264; Gonzalez-Fernandez et al. 1999. PubMed ID: 10617778). Functional studies have shown that the p.Gly238Trp substitution reduces enzyme activity by 90% (Yamamoto et al. 1999. PubMed ID: 10369264; Lidén et al. 2001. PubMed ID: 11675386). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret c.712G>T (p.Gly238Trp) as pathogenic. (less)
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Fundus albipunctatus Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161236.1 First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020
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Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.021%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:11675386). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.72). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008003). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID:10369264, 10617778). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate a damaging effect; variant causes reduced enzymatic activity and different staining pattern with a strong perinuclear localization for G238W mutant cells compared to wild type (Liden et al., 2001; Yamamoto et al., 1999); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31456290, 32141364, 17476461, 20829743, 10617778, 18949499, 10369264, 11675386)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 238 of the RDH5 protein (p.Gly238Trp). This variant is present in population databases (rs62638191, gnomAD 0.05%). This missense change has been observed in individuals with fundus albipunctatus (PMID: 10369264, 10617778). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8003). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RDH5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RDH5 function (PMID: 11675386). For these reasons, this variant has been classified as Pathogenic.

Comment:

The RDH5 c.712G>T variant is predicted to result in the amino acid substitution p.Gly238Trp. This variant has been reported in the homozygous and compound heterozygous states in individuals with autosomal recessive fundus albipunctatus (Yamamoto et al. 1999. PubMed ID: 10369264; Gonzalez-Fernandez et al. 1999. PubMed ID: 10617778). Functional studies have shown that the p.Gly238Trp substitution reduces enzyme activity by 90% (Yamamoto et al. 1999. PubMed ID: 10369264; Lidén et al. 2001. PubMed ID: 11675386). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret c.712G>T (p.Gly238Trp) 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
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
Phenotypic variability in RDH5 retinopathy (Fundus Albipunctatus).	Sergouniotis PI	Ophthalmology	2011	PMID: 21529959
Lack of autofluorescence in fundus albipunctatus associated with mutations in RDH5.	Schatz P	Retina (Philadelphia, Pa.)	2010	PMID: 20829743
Diagnosis in a patient with fundus albipunctatus and atypical fundus changes.	Hajali M	Documenta ophthalmologica. Advances in ophthalmology	2009	PMID: 18949499
Fundus albipunctatus in a 6-year old girl due to compound heterozygous mutations in the RDH5 gene.	Iannaccone A	Documenta ophthalmologica. Advances in ophthalmology	2007	PMID: 17476461
Biochemical defects in 11-cis-retinol dehydrogenase mutants associated with fundus albipunctatus.	Lidén M	The Journal of biological chemistry	2001	PMID: 11675386
11-cis retinol dehydrogenase mutations as a major cause of the congenital night-blindness disorder known as fundus albipunctatus.	Gonzalez-Fernandez F	Molecular vision	1999	PMID: 10617778
Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.	Yamamoto H	Nature genetics	1999	PMID: 10369264
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RDH5	-	-	-	-

Text-mined citations for rs62638191 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002905.5(RDH5):c.712G>T (p.Gly238Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62638191 ...