rs1555302200

Variant names:

• chr14-21326029-C-CTT
• rs1555302200
• NM_020366.4:c.2567_2568dupTT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020366.4(RPGRIP1):​c.2567_2568dupTT​(p.Val857LeufsTer2) 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 Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPGRIP1 NM_020366.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.398
• Publications: 0 publications found

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

• cone-rod dystrophy 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-21326029-C-CTT is Pathogenic according to our data. Variant chr14-21326029-C-CTT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523527.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. 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
	RPGRIP1	NM_020366.4	MANE Select	c.2567_2568dupTT	p.Val857LeufsTer2	frameshift	Exon 17 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.1493_1494dupTT	p.Val499LeufsTer2	frameshift	Exon 7 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.796+1305_796+1306dupTT		intron	N/A	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2567_2568dupTT	p.Val857LeufsTer2	frameshift	Exon 17 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.992_993dupTT	p.Val332LeufsTer2	frameshift	Exon 5 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.689-1593_689-1592dupTT		intron	N/A	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Color vision defect;C0271385:Horizontal nystagmus;C0854723:Retinal dystrophy;C3665347:Visual impairment (1)
1	-	-	Leber congenital amaurosis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555302200; hg19: chr14-21794188;