rs1553252388

Positions:

• chr1-215674563-GAGAGTCCATGTTC-GCAAG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4 PP5_Very_Strong

The NM_206933.4(USH2A):​c.13335_13347delGAACATGGACTCTinsCTTG​(p.Glu4445_Ser4449delinsAspLeu) variant causes a missense, disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E4445E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense, disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.09

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_206933.4.
• PP5: Variant 1-215674564-AGAGTCCATGTTC-CAAG is Pathogenic according to our data. Variant chr1-215674564-AGAGTCCATGTTC-CAAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense_variant, disruptive_inframe_deletion		ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense_variant, disruptive_inframe_deletion		1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.13335_13347delGAACATGGACTCTinsCTTG	p.Glu4445_Ser4449delinsAspLeu	missense_variant, disruptive_inframe_deletion				ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.13335_13347delinsCTTG variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3, PM4. Based on this evidence we have classified this variant as Likely Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	USH2A: PM3:Very Strong, PM1, PM2, PM4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2018	The c.13335_13347del13insCTTG variant in the USH2A gene has been reported previously in association with nonsyndromic retinitis pigmentosa (McGee et al., 2010). The c.13335_13347del13insCTTG variant causes an in-frame deletion of five amino acids and the insertion of two incorrect amino acids, denoted p.Glu4445_Ser4449delinsAspLeu. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The c.13335_13347del13insCTTG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.13335_13347del13insCTTG as a likely pathogenic variant. -

Usher syndrome type 2A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 17, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2022	- -

Retinitis pigmentosa Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553252388; hg19: chr1-215847906;