chr14-67729336-CGCCCT-C

Position:

• chr14-67729336-CGCCCT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_152443.3(RDH12):​c.806_810delCCCTG​(p.Ala269fs) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 7.79

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]

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]

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]

ZFYVE26 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.806_810delCCCTG	p.Ala269fs	frameshift_variant	8/9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.806_810delCCCTG	p.Ala269fs	frameshift_variant	8/9		XP_047286921.1
ZFYVE26	XM_047431173.1	c.*401_*405delAGGGC		3_prime_UTR_variant	42/42		XP_047287129.1
GPHN	XM_047430879.1	c.1313-5857_1313-5853delCCCTG		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.806_810delCCCTG	p.Ala269fs	frameshift_variant	8/9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.806_810delCCCTG	p.Ala269fs	frameshift_variant	7/8	5		ENSP00000267502.3
ZFYVE26	ENST00000394455.6	n.3158_3162delAGGGC		non_coding_transcript_exon_variant	14/15	2
RDH12	ENST00000552873.1	n.175_179delCCCTG		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152230 Hom.: 0 Cov.: 32

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: 42 AN: 239486 Hom.: 0 AF XY: 0.000153 AC XY: 20 AN XY: 130514

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.: 0 AF XY: 0.000178 AC XY: 128 AN XY: 720212

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: 16 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74506

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.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	research	Laboratory of Genetics in Ophthalmology, Institut Imagine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
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	clinical testing	Revvity Omics, Revvity	Jun 24, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2016	- -
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	- -

Leber congenital amaurosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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 -

RDH12-related disorder 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs386834261; hg19: chr14-68196053;