X-18642016-G-GC

Variant names:

• chrX-18642016-G-GC
• NM_000330.4:c.662dupG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000330.4(RS1):​c.662dupG​(p.Ser221ArgfsTer43) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RS1 NM_000330.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.11

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]

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0193 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-18642016-G-GC is Pathogenic according to our data. Variant chrX-18642016-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 3699831.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.662dupG	p.Ser221ArgfsTer43	frameshift_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.566dupG	p.Ser189ArgfsTer43	frameshift_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-3990dupC		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-3990dupC		intron_variant	Intron 18 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984.4	c.662dupG	p.Ser221ArgfsTer43	frameshift_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-3990dupC		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-3990dupC		intron_variant	Intron 18 of 20	1		ENSP00000369332.3
RS1	ENST00000476595.1	n.1153dupG		non_coding_transcript_exon_variant	Exon 5 of 5	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the RS1 gene (p.Ser221Argfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the RS1 protein and extend the protein by 38 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RS1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the RS1 protein in which other variant(s) (p.Cys223Arg) have been determined to be pathogenic (PMID: 10533068, 30652005; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: 1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-18660136;