rs780308389

Positions:

• chr1-216325393-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_206933.4(USH2A):​c.1055C>T​(p.Thr352Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.62

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 16 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 67 pathogenic changes around while only 10 benign (87%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-216325393-G-A is Pathogenic according to our data. Variant chr1-216325393-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216325393-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-216325393-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-216325393-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1055C>T	p.Thr352Ile	missense_variant	6/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1055C>T	p.Thr352Ile	missense_variant	6/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1055C>T	p.Thr352Ile	missense_variant	6/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.1055C>T	p.Thr352Ile	missense_variant	6/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.1055C>T	p.Thr352Ile	missense_variant	6/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250992 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135630

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000324 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.1055C>T 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, PM1-S. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33411470, 28653555, 31589614, 33576794, 35266249, 29142287, 17405132, 24498627, 25575603, 16963483, 18273898, 27460420, 34781295, 34948090, 28041643, 21569298) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 352 of the USH2A protein (p.Thr352Ile). This variant is present in population databases (rs780308389, gnomAD 0.002%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 17405132, 24498627, 25575603, 28653555, 29142287). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438002). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 26, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

USH2A-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 14, 2022	The c.1055C>T;p.(Thr352Ile) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 438002; PMID: 29142287; 28653555; 27460420; 25575603; 24498627; 21569298; 18273898; 17405132) - PS4. The variant is present at low allele frequencies population databases (rs780308389 - gnomAD 0.00007968%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr352Ile) was detected in trans with a pathogenic variant (PMID: 29142287; 28653555; 25575603; 24498627; 17405132) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 29142287) - PP1_moderate. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 16, 2024	The USH2A c.1055C>T variant is predicted to result in the amino acid substitution p.Thr352Ile. This variant was reported in the compound heterozygous or homozygous states in individuals with retinitis pigmentosa or Usher syndrome (Magliulo et al. 2017. PubMed ID: 28653555; Table S4 & S5, Colombo et al. 2021. PubMed ID: 33576794; Colombo et al. 2021. PubMed ID: 34781295; Table S2, Mansard et al. 2021. PubMed ID: 34948090; Table S1, Karali et al. 2022. PubMed ID: 36460718). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is listed in ClinVar as likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/438002/). This variant is interpreted as likely pathogenic. -

Usher syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 11, 2017

The p.Thr352Ile variant in USH2A has been reported in at least 7 individuals wit h Usher syndrome, 5 of whom carried a second pathogenic variant on the other all ele (Baux 2007, Cremers 2007, Dreyer 2008, Bonnet 2011, Besnard 2013, Lenarduzzi 2015, Bonnet 2016). This variant has also been identified in 2/111896 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinsti tute.org; dbSNP rs780308389). This frequency in the general population is low en ough to be consistent with a recessive carrier frequency for Usher syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosoma l recessive Usher syndrome based on multiple occurrences with a second pathogeni c variant in affected individuals. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.90		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.97
MPC		0.24
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.80
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs780308389; hg19: chr1-216498735;