rs750636662

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP2PP5

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. 13/22 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 0.364

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
hereditary hyperekplexia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

GPHN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_152443.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 53 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.14222 (below the threshold of 3.09). Trascript score misZ: 0.34257 (below the threshold of 3.09). GenCC associations: The gene is linked to RDH12-related recessive retinopathy, retinitis pigmentosa, Leber congenital amaurosis 13, Leber congenital amaurosis.

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 submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDH12	NM_152443.3 link	c.701G>A	p.Arg234His	missense_variant	Exon 8 of 9	ENST00000551171.6	NP_689656.2	Q96NR8A0A0S2Z613
RDH12	XM_047430965.1 link	c.701G>A	p.Arg234His	missense_variant	Exon 8 of 9		XP_047286921.1
ZFYVE26	XM_047431173.1 link	c.*509C>T		3_prime_UTR_variant	Exon 42 of 42		XP_047287129.1
GPHN	XM_047430879.1 link	c.1313-5962G>A		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.701G>A	p.Arg234His	missense_variant	Exon 8 of 9	1	NM_152443.3	ENSP00000449079.1	Q96NR8
RDH12	ENST00000267502.3 link	c.701G>A	p.Arg234His	missense_variant	Exon 7 of 8	5		ENSP00000267502.3	Q96NR8
ZFYVE26	ENST00000394455.6 link	n.3266C>T		non_coding_transcript_exon_variant	Exon 14 of 15	2
RDH12	ENST00000552873.1 link	n.70G>A		non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000925

AC:

AN:

248732

AF XY:

0.0000964

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1458818

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

725792

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33454

American (AMR)

AF:

0.000559

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.0000195

AC:

AN:

51156

Middle Eastern (MID)

AF:

0.000194

AC:

AN:

5158

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111984

Other (OTH)

AF:

0.0000166

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.000524

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00143

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000614

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leber congenital amaurosis 13

Pathogenic:4

May 04, 2022

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Mar 14, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis

Pathogenic:1Uncertain:1

Jan 30, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 09, 2022

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.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. -

not provided

Pathogenic:1Uncertain:1

Dec 04, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RDH12: PM3:Very Strong, PM2 -

Macular dystrophy

Pathogenic:1

Aug 01, 2019

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinal dystrophy

Uncertain:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Clinical significance based on ACMG v2.0 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

7.3

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.42

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.70

.;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.7

L;L

PhyloP100

0.36

PrimateAI

Benign

0.25

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

GERP RS

-0.56

Varity_R

0.033

gMVP

0.67

Mutation Taster

=11/89

disease causing

(source)

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

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rs750636662

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over