rs386834261

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_152443.3(RDH12):c.806_810delCCCTG(p.Ala269GlyfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,599,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

RDH12
NM_152443.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 7.79

Variant links:

Genes affected

RDH12 (HGNC:19977): (retinol dehydrogenase 12) The protein encoded by this gene is an NADPH-dependent retinal reductase whose highest activity is toward 9-cis and all-trans-retinol. The encoded enzyme also plays a role in the metabolism of short-chain aldehydes but does not exhibit steroid dehydrogenase activity. Defects in this gene are a cause of Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53. [provided by RefSeq, Sep 2015]

RDH12 links:

ZFYVE26 (HGNC:20761): (zinc finger FYVE-type containing 26) This gene encodes a protein which contains a FYVE zinc finger binding domain. The presence of this domain is thought to target these proteins to membrane lipids through interaction with phospholipids in the membrane. Mutations in this gene are associated with autosomal recessive spastic paraplegia-15. [provided by RefSeq, Oct 2008]

ZFYVE26 links:

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

GPHN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PP5

Variant 14-67729336-CGCCCT-C is Pathogenic according to our data. Variant chr14-67729336-CGCCCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67729336-CGCCCT-C is described in Lovd as [Pathogenic]. Variant chr14-67729336-CGCCCT-C is described in Lovd as [Likely_pathogenic]. Variant chr14-67729336-CGCCCT-C is described in Lovd as [Likely_pathogenic]. Variant chr14-67729336-CGCCCT-C is described in Lovd as [Pathogenic]. Variant chr14-67729336-CGCCCT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3 link	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift_variant	Exon 8 of 9	ENST00000551171.6	NP_689656.2	Q96NR8A0A0S2Z613
RDH12	XM_047430965.1 link	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift_variant	Exon 8 of 9		XP_047286921.1
ZFYVE26	XM_047431173.1 link	c.401_405delAGGGC		3_prime_UTR_variant	Exon 42 of 42		XP_047287129.1
GPHN	XM_047430879.1 link	c.1313-5857_1313-5853delCCCTG		intron_variant	Intron 14 of 14		XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RDH12	ENST00000551171.6 link	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift_variant	Exon 8 of 9	1	NM_152443.3	ENSP00000449079.1	Q96NR8
RDH12	ENST00000267502.3 link	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift_variant	Exon 7 of 8	5		ENSP00000267502.3	Q96NR8
ZFYVE26	ENST00000394455.6 link	n.3158_3162delAGGGC		non_coding_transcript_exon_variant	Exon 14 of 15	2
RDH12	ENST00000552873.1 link	n.175_179delCCCTG		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

239486

Hom.:

AF XY:

0.000153

AC XY:

AN XY:

130514

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000314

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000188

AC:

272

AN:

1446770

Hom.:

AF XY:

0.000178

AC XY:

128

AN XY:

720212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000230

Gnomad4 OTH exome

AF:

0.000150

GnomAD4 genome

AF:

0.000105

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000128

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:9Other:1

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

hom -

Laboratory of Genetics in Ophthalmology, Institut Imagine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 24, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala269Glyfs*2) in the RDH12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 48 amino acid(s) of the RDH12 protein. This variant is present in population databases (rs758435713, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with autosomal recessive Leber congenital amaurosis (PMID: 17389517, 22065924, 23847139). ClinVar contains an entry for this variant (Variation ID: 2047). This variant disrupts a region of the RDH12 protein in which other variant(s) (p.Arg295*) have been determined to be pathogenic (PMID: 16269441, 22065924, 26047050). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000002047 /PMID: 15258582). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The RDH12 c.806_810del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PS3, PP1-S, PM2. Based on this evidence we have classified this variant as Pathogenic. -

not provided

Pathogenic:3

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 48 amino acids are lost and replaced with 1 incorrect amino acid; This variant is associated with the following publications: (PMID: 17512964, 32531858, 15258582, 20683928, 20301475, 17964524, 23847139, 15322982, 19011012, 16269441, 26667666, 30372751, 22065924, 31424981, 30979730, 30653986, 32036094, 32581362, 31589614, 32865313) -

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leber congenital amaurosis

Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RDH12 c.806_810delCCCTG (p.Ala269GlyfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00018 in 239486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (0.00018 vs 0.0016), allowing no conclusion about variant significance. c.806_810delCCCTG has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis and the variant segregated with the disease in four families (e.g. Aleman_2018, Wang_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant causes absent protein expression and a dramatic reduction in activity (Sun_2007). The following publications have been ascertained in the context of this evaluation (PMID: 30372751, 17512964, 23847139). ClinVar contains an entry for this variant (Variation ID: 2047). Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:2

May 22, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Abnormality of the eye

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Rare ocular disorder associated to additional undetermined phenotypes -

Retinitis pigmentosa

Pathogenic:1

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RDH12-related disorder

Pathogenic:1

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RDH12 c.806_810delCCCTG (p.Ala269GlyfsTer2) variant results in a frameshift and is predicted to result in premature truncation of the protein. Across a selection of the available literature, the p.Ala269GlyfsTer2 variant has been found in at least 18 individuals affected with retinal disorders, including in 12 in a compound heterozygous state, in five in a homozygous state and in one in a heterozygous state (Perrault et al. 2004; Thompson et al. 2005; Coppieters et al. 2010; Wang et al. 2013; Boulanger-Scemama et al. 2015; Ge et al. 2015). The p.Ala269GlyfsTer2 variant was absent from at least 699 controls (Perrault et al. 2004; Coppieters et al. 2010; Sun et al. 2007) and is reported at a frequency of 0.0003 in the European (non-Finnish) population of the Genome Aggregation Database. The functional effect of the variant was assayed by transfection in COS-7 cells, which led to undetectable levels of RDH12 expression, and a dramatic reduction in ability to produce all-trans-retinol from all-trans-retinal, as compared to wild type (Sun et al. 2007). Based on the collective evidence, the p.Ala269GlyfsTer2 variant is classified as pathogenic for RDH12-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over