rs886039450

chr1-216207400-TTG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_206933.4(USH2A):c.3187_3188del(p.Gln1063SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,924 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

USH2A
NM_206933.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 1.78

Variant links:

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]

USH2A links:

USH2A-AS1 (HGNC:):

USH2A-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 1-216207400-TTG-T is Pathogenic according to our data. Variant chr1-216207400-TTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 265288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216207400-TTG-T is described in Lovd as [Pathogenic]. Variant chr1-216207400-TTG-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
USH2A	NM_206933.4 linkuse as main transcript	c.3187_3188del	p.Gln1063SerfsTer15	frameshift_variant	16/72	ENST00000307340.8
USH2A-AS1	XR_922596.4 linkuse as main transcript	n.691+11477_691+11478del		intron_variant, non_coding_transcript_variant
USH2A	NM_007123.6 linkuse as main transcript	c.3187_3188del	p.Gln1063SerfsTer15	frameshift_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.3187_3188del	p.Gln1063SerfsTer15	frameshift_variant	16/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.3187_3188del	p.Gln1063SerfsTer15	frameshift_variant	16/21	1			O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.3187_3188del	p.Gln1063SerfsTer15	frameshift_variant	16/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461736

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000279

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 31, 2022	PM2, PM3_strong, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2019	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 a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25472526, 15325563, 27624628, 23924366) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Dec 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This sequence change creates a premature translational stop signal (p.Gln1063Serfs*15) 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). This variant is present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with retinitis pigemntosa and/or Usher syndrome type 2 (PMID: 23924366, 25472526). ClinVar contains an entry for this variant (Variation ID: 265288). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.3187_3188del 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: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 18, 2018	- -

Usher syndrome type 2A

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 18, 2018	- -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 07, 2018

The p.Gln1036fs variant in USH2A has been reported in >5 individuals with Usher syndrome or retinitis pigmentosa (RP), all of whom were homozygous or compound heterozygous (Sandberg 2008, Le Quesne Stabej 2012, Steele-Stallard 2013, Zhao 2015, Carrigan 2016, LMM data). It has also been identified in 1/8732 African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1063 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the USH2A gene is an established disease mechanism in autosomal recessive Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PVS1; PMS3_VeryStrong. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Mar 30, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over