rs267607006

Positions:

• chr12-55724515-CC-CGAAG

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_002905.5(RDH5):​c.928delinsGAAG​(p.Leu310delinsGluVal) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH5 NM_002905.5 protein_altering
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.904

Genes affected

RDH5 (HGNC:9940): (retinol dehydrogenase 5) This gene encodes an enzyme belonging to the short-chain dehydrogenases/reductases (SDR) family. This retinol dehydrogenase functions to catalyze the final step in the biosynthesis of 11-cis retinaldehyde, which is the universal chromophore of visual pigments. Mutations in this gene cause autosomal recessive fundus albipunctatus, a rare form of night blindness that is characterized by a delay in the regeneration of cone and rod photopigments. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring upstream BLOC1S1 (biogenesis of lysosomal organelles complex-1, subunit 1) gene. [provided by RefSeq, Dec 2010]

BLOC1S1-RDH5 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002905.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-55724516-C-GAAG is Pathogenic according to our data. Variant chr12-55724516-C-GAAG is described in ClinVar as [Pathogenic]. Clinvar id is 8009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RDH5	NM_002905.5	c.928delinsGAAG	p.Leu310delinsGluVal	protein_altering_variant	5/5	ENST00000257895.10
BLOC1S1-RDH5	NR_037658.1	n.987delinsGAAG		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH5	ENST00000257895.10	c.928delinsGAAG	p.Leu310delinsGluVal	protein_altering_variant	5/5	1	NM_002905.5	P1
RDH5	ENST00000548082.1	c.928delinsGAAG	p.Leu310delinsGluVal	protein_altering_variant	5/5	1		P1
RDH5	ENST00000547072.5	c.637delinsGAAG	p.Leu213delinsGluVal	protein_altering_variant	5/5	5
RDH5	ENST00000551444.1	n.878delinsGAAG		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2017	The c.928delCinsGAAG variant has been reported previously in association with fundus albipunctatus (Nakamura et al., 2000, Niwa et al., 2005). The variant results in the in-frame replacement of the Leucine at position 310 with a Glutamic acid and a Valine residue. Functional studies have shown this variant results in reduced protein stability and activity levels as well as abnormal expression patterns (Lidén et al., 2001). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects RDH5 function (PMID: 11675386). 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. ClinVar contains an entry for this variant (Variation ID: 882948). This variant has been observed in individual(s) with fundus albipunctatus (PMID: 11053295, 15007239, 28393863). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant, c.928delinsGAAG, is a complex sequence change that results in the deletion of 1 and insertion of 2 amino acid(s) in the RDH5 protein ( p.Leu310delinsGluVal). -

Fundus albipunctatus, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs267607006; hg19: chr12-56118300;