rs386834261

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_152443.3(RDH12):c.806_810del(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 (★★). Synonymous variant affecting the same amino acid position (i.e. A269A) has been classified as Likely benign.

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:17O: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:):

GPHN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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 26 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/exons	MANE
RDH12	NM_152443.3 linkuse as main transcript	c.806_810del	p.Ala269GlyfsTer2	frameshift_variant	8/9	ENST00000551171.6
RDH12	XM_047430965.1 linkuse as main transcript	c.806_810del	p.Ala269GlyfsTer2	frameshift_variant	8/9
ZFYVE26	XM_047431173.1 linkuse as main transcript	c.401_405del		3_prime_UTR_variant	42/42
GPHN	XM_047430879.1 linkuse as main transcript	c.1313-5857_1313-5853del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
RDH12	ENST00000551171.6 linkuse as main transcript	c.806_810del	p.Ala269GlyfsTer2	frameshift_variant	8/9	1	NM_152443.3	P1
RDH12	ENST00000267502.3 linkuse as main transcript	c.806_810del	p.Ala269GlyfsTer2	frameshift_variant	7/8	5		P1
ZFYVE26	ENST00000394455.6 linkuse as main transcript	n.3158_3162del		non_coding_transcript_exon_variant	14/15	2
RDH12	ENST00000552873.1 linkuse as main transcript	n.175_179del		non_coding_transcript_exon_variant	2/2	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:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	This sequence change creates a premature translational stop signal (p.Ala269Glyfs2) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 18, 2023	hom -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2021	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 22, 2019	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Abnormality of the eye

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

Rare ocular disorder associated to additional undetermined phenotypes -

Leber congenital amaurosis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

RDH12-Related Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 15, 2018

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. -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Sep 01, 2016

- -

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