rs751176116

chr1-215900144-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_206933.4(USH2A):c.7524del(p.Arg2509GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,514 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 0.202

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 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 1-215900144-GA-G is Pathogenic according to our data. Variant chr1-215900144-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 517494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215900144-GA-G is described in Lovd as [Pathogenic]. Variant chr1-215900144-GA-G is described in Lovd as [Pathogenic]. Variant chr1-215900144-GA-G is described in Lovd as [Likely_pathogenic]. Variant chr1-215900144-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.7524del	p.Arg2509GlyfsTer19	frameshift_variant	40/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.7524del	p.Arg2509GlyfsTer19	frameshift_variant	40/72	1	NM_206933.4	P1
	ENST00000414995.1	n.61-578del		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.7524del	p.Arg2509GlyfsTer19	frameshift_variant	40/73

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250734 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461514 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21569298, 27957503, 27460420, 25333064) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 11, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 517494). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 21569298, 25333064, 27460420, 27957503). This variant is present in population databases (rs751176116, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg2509Glyfs*19) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). -

Retinitis pigmentosa 39 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.7524del 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, PVS1, PM3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2023	- -

Usher syndrome type 2A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 23, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM1,PM2,PP5. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 26, 2023

Variant summary: USH2A c.7524delT (p.Arg2509GlyfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 250734 control chromosomes. c.7524delT has been reported in the literature in individuals affected with Usher Syndrome (e.g. Bonnet_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 21569298). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 25, 2017

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2017

The p.Arg2509fs variant in USH2A has been reported in the compound heterozygous state in at least two individuals with Usher syndrome (Bonnet 2011, Krawitz 2014 , Bonnet 2016). It has been identified in 1/111126 European chromosomes by the G enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs7 51176116). Although this variant has been seen in the general population, its fr equency is low enough to be consistent with a recessive carrier frequency for Us her syndrome. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2509 and leads to a prematur e termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established di sease mechanism for autosomal recessive Usher syndrome. In summary, the p.Arg25 09fs variant meets criteria to be classified as pathogenic for autosomal recessi ve Usher syndrome based on the predicted impact of the variant and compound hete rozygosity with other pathogenic USH2A variants in individuals with Usher syndro me. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs751176116; hg19: chr1-216073486;