rs104894935

Positions:

• chrX-18672031-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000330.4(RS1):​c.38T>C​(p.Leu13Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RS1 NM_000330.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.34

Genes affected

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-18672031-A-G is Pathogenic according to our data. Variant chrX-18672031-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-18672031-A-G is described in Lovd as [Pathogenic]. Variant chrX-18672031-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RS1	NM_000330.4	c.38T>C	p.Leu13Pro	missense_variant	1/6	ENST00000379984.4	NP_000321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.38T>C	p.Leu13Pro	missense_variant	1/6	1	NM_000330.4	ENSP00000369320.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2020	This variant has been observed in individual(s) with retinoschisis (PMID: 10533068, 30652005, 20809529, Invitae). ClinVar contains an entry for this variant (Variation ID: 9892). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects RS1 protein function (PMID: 20809529). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 13 of the RS1 protein (p.Leu13Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2023	Published functional studies demonstrate a damaging effect on expression, consistent with a null allele (PMID: 20809529, 12746437); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12746437, 36402656, 10533068, 20809529, 22183371, 22245536, 30652005) -
not provided, no classification provided	literature only	Retina International	-	- -

Juvenile retinoschisis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.86	N
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.98	D
Vest4		0.92
MutPred		0.84		Gain of sheet (P = 0.0028);
MVP		1.0
MPC		1.2
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.62
gMVP		0.93

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: rs104894935; hg19: chrX-18690151;