NM_000539.3:c.68C>A

Variant names:

• chr3-129528801-C-A
• rs104893768
• NM_000539.3:c.68C>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000539.3(RHO):​c.68C>A​(p.Pro23His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000576880: Published functional studies demonstrate a damaging effect with impaired function and decreased thermal stability of the RHO protein as well as increased photoreceptor cell death (Noorwez et al., 2004" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P23A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHO NM_000539.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.90
• Publications: 879 publications found

Genes affected

RHO (HGNC:10012): (rhodopsin) The protein encoded by this gene is found in rod cells in the back of the eye and is essential for vision in low-light conditions. The encoded protein binds to 11-cis retinal and is activated when light hits the retinal molecule. Defects in this gene are a cause of congenital stationary night blindness. [provided by RefSeq, Aug 2017]

RHO Gene-Disease associations (from GenCC):

• congenital stationary night blindness autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• inherited retinal dystrophy

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 4

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fundus albipunctatus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000576880: Published functional studies demonstrate a damaging effect with impaired function and decreased thermal stability of the RHO protein as well as increased photoreceptor cell death (Noorwez et al., 2004; Comitato et al., 2016); SCV000884459: "functional studies in a mouse model show this variant causes altered function" (Comitato A et al. Dominant and recessive mutations in rhodopsin activate different cell death pathways. Hum Mol Genet. 2016 Jul 1;25(13):2801-2812.); SCV001205315: Experimental studies have shown that this missense change affects RHO function (PMID: 1418997, 19913029, 22323724, 24853414).; SCV005345275: Several functional studies have shown that the p.Pro23His substitution decreases both protein stability and activity (see for example Krebs et al. 2010. PubMed ID: 19913029).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_000539.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-129528800-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13055.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 125 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.24182 (below the threshold of 3.09). Trascript score misZ: 1.4363 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital stationary night blindness, retinitis pigmentosa 4, inherited retinal dystrophy, fundus albipunctatus, congenital stationary night blindness autosomal dominant 1, retinitis pigmentosa.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-129528801-C-A is Pathogenic according to our data. Variant chr3-129528801-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000539.3. 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
	RHO	NM_000539.3	MANE Select	c.68C>A	p.Pro23His	missense	Exon 1 of 5	NP_000530.1	P08100

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHO	ENST00000296271.4	TSL:1 MANE Select	c.68C>A	p.Pro23His	missense	Exon 1 of 5	ENSP00000296271.3	P08100

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000681 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Retinitis pigmentosa 4 (2)
1	-	-	Pigmentary retinal dystrophy;C1864869:Congenital stationary night blindness autosomal dominant 1;C3151001:Retinitis pigmentosa 4 (1)
1	-	-	Retinal dystrophy (1)
1	-	-	RHO-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.83		Gain of loop (P = 0.0435)
MVP		0.98
MPC		0.93
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.040	Neutral
Varity_R		0.99
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893768; hg19: chr3-129247644;