chr12-55724516-C-GAAG

Variant names:

• chr12-55724516-C-GAAG
• rs267607006
• NM_002905.5:c.928delCinsGAAG

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM2 PM4_Supporting PP5_Very_Strong

The NM_002905.5(RDH5):​c.928delCinsGAAG​(p.Leu310delinsGluVal) variant causes a missense, disruptive inframe insertion 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH5 NM_002905.5 missense, disruptive_inframe_insertion
• 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]

ENSG00000258311 (HGNC:):

CD63 (HGNC:1692): (CD63 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PS1: Transcript NM_002905.5 (RDH5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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 rank	MANE	Protein	UniProt
RDH5	NM_002905.5	c.928delCinsGAAG	p.Leu310delinsGluVal	missense_variant, disruptive_inframe_insertion	Exon 5 of 5	ENST00000257895.10	NP_002896.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH5	ENST00000257895.10	c.928delCinsGAAG	p.Leu310delinsGluVal	missense_variant, disruptive_inframe_insertion	Exon 5 of 5	1	NM_002905.5	ENSP00000257895.6
ENSG00000258311	ENST00000550412.5	c.*2810delCinsGAAG		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000447650.1

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

Aug 23, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs761500612, gnomAD 0.07%). 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. ClinVar contains an entry for this variant (Variation ID: 882948). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 variant affects RDH5 function (PMID: 11675386). For these reasons, this variant has been classified as Pathogenic. -

Fundus albipunctatus, autosomal recessive Pathogenic:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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;