rs750636662

Positions:

• chr14-67729233-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP5

The NM_152443.3(RDH12):​c.701G>A​(p.Arg234His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,610,986 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: RDH12 NM_152443.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4
• Conservation: PhyloP100: 0.364

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_152443.3
• PP5: Variant 14-67729233-G-A is Pathogenic according to our data. Variant chr14-67729233-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 313842.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=1, Pathogenic=3}. Variant chr14-67729233-G-A is described in Lovd as [Pathogenic]. Variant chr14-67729233-G-A is described in Lovd as [Pathogenic]. Variant chr14-67729233-G-A is described in Lovd as [Likely_pathogenic]. Variant chr14-67729233-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RDH12	NM_152443.3	c.701G>A	p.Arg234His	missense_variant	8/9	ENST00000551171.6
RDH12	XM_047430965.1	c.701G>A	p.Arg234His	missense_variant	8/9
ZFYVE26	XM_047431173.1	c.*509C>T		3_prime_UTR_variant	42/42
GPHN	XM_047430879.1	c.1313-5962G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDH12	ENST00000551171.6	c.701G>A	p.Arg234His	missense_variant	8/9	1	NM_152443.3	P1
RDH12	ENST00000267502.3	c.701G>A	p.Arg234His	missense_variant	7/8	5		P1
ZFYVE26	ENST00000394455.6	n.3266C>T		non_coding_transcript_exon_variant	14/15	2
RDH12	ENST00000552873.1	n.70G>A		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.0000925 AC: 23 AN: 248732 Hom.: 0 AF XY: 0.0000964 AC XY: 13 AN XY: 134806

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000636

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1458818 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 725792

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 234 of the RDH12 protein (p.Arg234His). This variant is present in population databases (rs750636662, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive macular or retinal dystrophy (PMID: 19011012, 30979730; Invitae). 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: 313842). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RDH12 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RDH12 function (PMID: 16269441). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2024	- -

Leber congenital amaurosis Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 30, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2022	Variant summary: RDH12 c.701G>A (p.Arg234His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 248732 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RDH12 causing Leber Congenital Amaurosis (9.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.701G>A has been reported in the literature as biallelic compound heterozygous genotypes in multiple individuals affected with features of RDH12-related retinal dystrophy (example, Thompson_2005, Valverde_2009, Mendez-Vidal_2014, Glockle_2014, Avila-Fernandez_2010, Martin-Merida_2019, Ba-Abbad_2020, De Zaeytijd_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 44% of normal retinoid reductase activity (Thompson_2005). A threshold effect resulting from co-inheritance with another loss of function (LOF) variant, combined with a reduction in p.R234H activity to less than half of wild-type, resulting in insufficient RDH12 enzyme levels for normal visual cycle function has been proposed (Thompson_2005). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -

Macular dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Ocular Genomics Institute, Massachusetts Eye and Ear

Aug 01, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In vitro functional studies demonstrated that R234H retained 44% enzyme activity level compared to wild type (Thompson et al., 2005); Observed with a missense variant on the opposite allele (in trans) in individuals with retinal dystrophy in published literature (Thompson et al., 2005; Avila-Fernandez et al., 2010; Consugar et al., 2015); This variant is associated with the following publications: (PMID: 25412400, 16269441, 19011012, 21151602, 25494902, 32790509) -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

The RDH12 c.701G>A (p.Arg234His) missense variant has been identified in at least four studies in which it is found in at least four patients, including at least two individuals with an autosomal recessive form of retinitis pigmentosa (RP) and one individual with macular dystrophy, all three of whom carried the variant in a compound heterozygous state. A fourth individual with RP carried the p.Arg234His variant in a heterozygous state along with a homozygous missense variant in another gene associated with RP, so the contribution of the p.Arg234His variant to disease in this patient is unclear ((Thompson et al. 2005; Ávila-Fernández et al. 2010; Consugar et al. 2014; Méndez-Vidal et al. 2014). Control data are unavailable for the p.Arg234His variant, which is reported at a frequency of 0.00095 in the Latino population of the Exome Aggregation Consortium. Functional analysis in COS-7 cells demonstrated that in the presence of some substrates, protein activity was 44% in cells transfected with the p.Arg234His variant compared to wild type, although notably the p.Arg234His demonstrated a higher activity level than the other variants assessed (Thompson et al. 2005). Further, the variant protein was expressed at levels similar to wild type when assayed by Western blotting and immunohistochemistry, leading the authors to suggest the variant may not be disease-causing. Based on the evidence, the p.Arg234His variant is classified as a variant of unknown significance, but suspicious for pathogenicity for retinitis pigmentosa. 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	7.3
DANN	Benign	0.96
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.26	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;B
Vest4		0.70
MutPred		0.76		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);
MVP		0.95
MPC		0.28
ClinPred		0.075	T
GERP RS		-0.56
Varity_R		0.033
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs750636662; hg19: chr14-68195950;