rs780779563

Positions:

• chr1-216418618-CTT-C

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.545_546del​(p.Lys182ArgfsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K182K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.83

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 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 1-216418618-CTT-C is Pathogenic according to our data. Variant chr1-216418618-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 556324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216418618-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.545_546del	p.Lys182ArgfsTer33	frameshift_variant	3/72	ENST00000307340.8
USH2A	NM_007123.6	c.545_546del	p.Lys182ArgfsTer33	frameshift_variant	3/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.545_546del	p.Lys182ArgfsTer33	frameshift_variant	3/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.545_546del	p.Lys182ArgfsTer33	frameshift_variant	3/21	1
USH2A	ENST00000674083.1	c.545_546del	p.Lys182ArgfsTer33	frameshift_variant	3/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250896 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135594

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: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461098 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726850

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2018	The c.545_546delAA variant in the USH2A gene has been reported previously in association with autosomal recessive Usher syndrome type II (Sayedahmadi et al., 2004; Hartel et al., 2016). In addition, the c.545_546delAA variant has been reported in an individual with retinitis pigmentosa who also had another frameshift variant in the USH2A gene (Sandberg et al., 2008). The c.545_546delAA variant causes a frameshift starting with codon Lysine 182, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 33 of the new reading frame, denoted p.Lys182ArgfsX33. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.545_546delAA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.545_546delAA as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change creates a premature translational stop signal (p.Lys182Argfs*33) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Usher syndrome type II (PMID: 15325563, 18273898, 27318125). ClinVar contains an entry for this variant (Variation ID: 556324). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 24, 2018

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs780779563; hg19: chr1-216591960;