rs397518008

chr1-216232047-TC-T

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.2898del(p.Thr967LeufsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,750 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. L966L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.676

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-AS1 (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 1-216232047-TC-T is Pathogenic according to our data. Variant chr1-216232047-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 2352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216232047-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.2898del	p.Thr967LeufsTer44	frameshift_variant	14/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.800-5787del		intron_variant, non_coding_transcript_variant
USH2A	NM_007123.6	c.2898del	p.Thr967LeufsTer44	frameshift_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.2898del	p.Thr967LeufsTer44	frameshift_variant	14/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.2898del	p.Thr967LeufsTer44	frameshift_variant	14/21	1
USH2A	ENST00000674083.1	c.2898del	p.Thr967LeufsTer44	frameshift_variant	14/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727180

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: 8.99e-7

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

Usher syndrome type 2A Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Retinitis pigmentosa 39 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2023	- -
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

Dec 24, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2023

This sequence change creates a premature translational stop signal (p.Thr967Leufs*44) 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 Usher syndrome type IIa (PMID: 9624053). This variant is also known as 2913delG. ClinVar contains an entry for this variant (Variation ID: 2352). For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 05, 2012

The Thr967fs variant in USH2A has been reported in at least three individuals wi th Usher syndrome, two of whom were homozygous, and was found to segregate with disease in one affected family member (Eudy 1998, Weston 2000, Seyedahmadi 2004, Jaijo 2010). This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 967 and lead to a premature termination cod on 44 amino acids downstream. This alteration is then predicted to lead to a tru ncated or absent protein. In summary, this variant meets our criteria to be clas sified as pathogenic (http://pcpgm.partners.org/LMM). -

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: rs397518008; hg19: chr1-216405389;