rs104894474

Positions:

• chr14-67726086-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152443.3(RDH12):​c.379G>T​(p.Gly127*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDH12 NM_152443.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 10.0

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-67726086-G-T is Pathogenic according to our data. Variant chr14-67726086-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67726086-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.379G>T	p.Gly127*	stop_gained	6/9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.379G>T	p.Gly127*	stop_gained	6/9		XP_047286921.1
GPHN	XM_047430879.1	c.1313-9109G>T		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.379G>T	p.Gly127*	stop_gained	6/9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.379G>T	p.Gly127*	stop_gained	5/8	5		ENSP00000267502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:4

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	Mar 05, 2019	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RDH12 are known to be pathogenic (PMID: 17964524, 22065924). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individuals affected with retinal dystrophies (PMID: 15322982, 17389517, 26355662). ClinVar contains an entry for this variant (Variation ID: 2051). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly127*) in the RDH12 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	This variant has not been reported in the literature in individuals affected with RDH12-related conditions and Iranom. The 14 years old boy whit vision problem has been detected homozygous c.379G>T mutation on his RDH12 genes and the parents are first cousin. The RDH12 gene is associated whit autosomal recessive Leber congenital amaurosis 13/retinitis pigmentosa therefore he is affected to this disease. Therefore, it has been classified as a Variant of Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2019

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Apr 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.80
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894474; hg19: chr14-68192803;