rs28940314

Positions:

• chr14-67724550-C-A
• chr14-67724550-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_152443.3(RDH12):​c.146C>A​(p.Thr49Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T49M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RDH12 NM_152443.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.70

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 16 ACMG points.

• PM1: In a binding_site (size 6) in uniprot entity RDH12_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_152443.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-67724550-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 14-67724550-C-A is Pathogenic according to our data. Variant chr14-67724550-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1037561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-67724550-C-A is described in Lovd as [Pathogenic]. Variant chr14-67724550-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDH12	NM_152443.3	c.146C>A	p.Thr49Lys	missense_variant	4/9	ENST00000551171.6	NP_689656.2
RDH12	XM_047430965.1	c.146C>A	p.Thr49Lys	missense_variant	4/9		XP_047286921.1
GPHN	XM_047430879.1	c.1313-10645C>A		intron_variant			XP_047286835.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDH12	ENST00000551171.6	c.146C>A	p.Thr49Lys	missense_variant	4/9	1	NM_152443.3	ENSP00000449079.1
RDH12	ENST00000267502.3	c.146C>A	p.Thr49Lys	missense_variant	3/8	5		ENSP00000267502.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251484 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461714 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 13 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with RDH12 related disorder (PMID:22065924, PS1_P). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002049, PMID:15258582, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.777, 3CNET: 0.986, PP3_P). A missense variant is a common mechanism associated with Leber congenital amaurosis 13 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 18, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 14, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr49 amino acid residue in RDH12. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15258582, 20006610, 24474277). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1037561). This missense change has been observed in individuals with autosomal recessive RDH12-related conditions (PMID: 22065924, 30979730; Invitae). This variant is present in population databases (rs28940314, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 49 of the RDH12 protein (p.Thr49Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.99	D;D
Vest4		0.95
MutPred		0.65		Gain of methylation at T49 (P = 0.0061);Gain of methylation at T49 (P = 0.0061);
MVP		0.97
MPC		0.92
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.75

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: rs28940314; hg19: chr14-68191267;