chrX-154154602-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

OPN1LW
NM_020061.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.82

Publications

33 publications found

Variant links:

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: G2P, Orphanet
red color blindness
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OPN1LW links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPN1LW	NM_020061.6 link	c.607T>C	p.Cys203Arg	missense_variant	Exon 4 of 6	ENST00000369951.9	NP_064445.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OPN1LW	ENST00000369951.9 link	c.607T>C	p.Cys203Arg	missense_variant	Exon 4 of 6	1	NM_020061.6	ENSP00000358967.4	P04000
OPN1LW	ENST00000442922.1 link	c.196T>C	p.Cys66Arg	missense_variant	Exon 2 of 4	5		ENSP00000402493.1	H0Y622
OPN1LW	ENST00000463296.1 link	n.588+1494T>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.29e-7

AC:

AN:

1076532

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

345470

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26115

American (AMR)

AF:

0.00

AC:

AN:

34436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18837

East Asian (EAS)

AF:

0.00

AC:

AN:

29950

South Asian (SAS)

AF:

0.00

AC:

AN:

53302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39863

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

824694

Other (OTH)

AF:

0.00

AC:

AN:

45291

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jul 19, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

One of the most common pathogenic variants associated with blue cone monochromacy (Buena-Atienza et al., 2016); Functional studies demonstrate loss of cone opsin function with misfolded opsins that are retained in the endoplasmic reticulum and degraded (Kazmi et al., 1997); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27274860, 22998501, 23139274, 23322568, 25168334, 2788922, 8666378, 27447086, 15094734, 9152227, 30516820, 27339364) -

Cone monochromatism

Pathogenic:1

Jan 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Protan defect

Pathogenic:1

Oct 21, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.39

PhyloP100

7.8

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-11

D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.99

MutPred

0.94

Gain of disorder (P = 0.003);.;

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

4.3

gMVP

1.0

Mutation Taster

=25/75

disease causing (ClinVar)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over