rs386834261

Variant names:

• chr14-67729336-CGCCCT-C
• rs386834261
• NM_152443.3:c.806_810delCCCTG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_152443.3(RDH12):​c.806_810delCCCTG​(p.Ala269GlyfsTer2) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000915647: 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)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A269A) has been classified as Likely benign.

• 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:19 O:1
• Conservation: PhyloP100: 7.79
• Publications: 21 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 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 20 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915647: 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).; SCV005077079: "At least one publication reports experimental evidence that this variant causes absent protein expression and a dramatic reduction in activity (Sun_2007)."
• PP5: Variant 14-67729336-CGCCCT-C is Pathogenic according to our data. Variant chr14-67729336-CGCCCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152443.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	NM_152443.3	MANE Select	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift	Exon 8 of 9	NP_689656.2	A0A0S2Z613

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDH12	ENST00000551171.6	TSL:1 MANE Select	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift	Exon 8 of 9	ENSP00000449079.1	Q96NR8
	RDH12	ENST00000267502.3	TSL:5	c.806_810delCCCTG	p.Ala269GlyfsTer2	frameshift	Exon 7 of 8	ENSP00000267502.3	Q96NR8
	ZFYVE26	ENST00000394455.6	TSL:2	n.3158_3162delAGGGC		non_coding_transcript_exon	Exon 14 of 15

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

GnomAD2 exomes AF: 0.000175 AC: 42 AN: 239486 AF XY: 0.000153

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.000157 AC: 7 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4164

European-Non Finnish (NFE) AF: 0.000230 AC: 256 AN: 1111810

Other (OTH) AF: 0.000150 AC: 9 AN: 60138

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000128

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Leber congenital amaurosis 13 (10)
3	-	-	not provided (3)
2	-	-	Leber congenital amaurosis (2)
2	-	-	Retinal dystrophy (2)
1	-	-	Abnormality of the eye (1)
1	-	-	RDH12-related disorder (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386834261; hg19: chr14-68196053;