rs121434621

Variant names:

• chrX-154154602-T-C
• rs121434621
• NM_020061.6:c.607T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_020061.6(OPN1LW):​c.607T>C​(p.Cys203Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,076,532 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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: "SCV000566961: Functional studies demonstrate loss of cone opsin function with misfolded opsins that are retained in the endoplasmic reticulum and degraded (Kazmi et al., 1997)".

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: OPN1LW NM_020061.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.82
• Publications: 33 publications found

Genes affected

OPN1LW (HGNC:9936): (opsin 1, long wave sensitive) This gene encodes for a light absorbing visual pigment of the opsin gene family. The encoded protein is called red cone photopigment or long-wavelength sensitive opsin. Opsins are G-protein coupled receptors with seven transmembrane domains, an N-terminal extracellular domain, and a C-terminal cytoplasmic domain. This gene and the medium-wavelength opsin gene are tandemly arrayed on the X chromosome and frequent unequal recombination and gene conversion may occur between these sequences. X chromosomes may have fusions of the medium- and long-wavelength opsin genes or may have more than one copy of these genes. Defects in this gene are the cause of partial, protanopic colorblindness. [provided by RefSeq, Jul 2008]

OPN1LW Gene-Disease associations (from GenCC):

• blue cone monochromacy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• red color blindness

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000566961: Functional studies demonstrate loss of cone opsin function with misfolded opsins that are retained in the endoplasmic reticulum and degraded (Kazmi et al., 1997)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-154154602-T-C is Pathogenic according to our data. Variant chrX-154154602-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020061.6. 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
	OPN1LW	NM_020061.6	MANE Select	c.607T>C	p.Cys203Arg	missense	Exon 4 of 6	NP_064445.2	P04000

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPN1LW	ENST00000369951.9	TSL:1 MANE Select	c.607T>C	p.Cys203Arg	missense	Exon 4 of 6	ENSP00000358967.4	P04000
	OPN1LW	ENST00000442922.1	TSL:5	c.196T>C	p.Cys66Arg	missense	Exon 2 of 4	ENSP00000402493.1	H0Y622
	OPN1LW	ENST00000463296.1	TSL:5	n.588+1494T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076532 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 345470

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26115

American (AMR) AF: 0.00 AC: 0 AN: 34436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18837

East Asian (EAS) AF: 0.00 AC: 0 AN: 29950

South Asian (SAS) AF: 0.00 AC: 0 AN: 53302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39863

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 824694

Other (OTH) AF: 0.00 AC: 0 AN: 45291

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 16

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Cone monochromatism (1)
1	-	-	Protan defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.39	D
PhyloP100		7.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.99
MutPred		0.94		Gain of disorder (P = 0.003)
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
gMVP		1.0
Mutation Taster		=25/75	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: rs121434621; hg19: chrX-153420077;