rs527236137

chr1-215674901-G-Achr1-215674901-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_206933.4(USH2A):c.13010C>T(p.Thr4337Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,864 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4337K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.56

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215674901-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2001506.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 1-215674901-G-A is Pathogenic according to our data. Variant chr1-215674901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215674901-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-215674901-G-A is described in Lovd as [Pathogenic]. Variant chr1-215674901-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.13010C>T	p.Thr4337Met	missense_variant	63/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.13010C>T	p.Thr4337Met	missense_variant	63/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.13010C>T	p.Thr4337Met	missense_variant	63/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461864 Hom.: 0 Cov.: 37 AF XY: 0.0000124 AC XY: 9 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4337 of the USH2A protein (p.Thr4337Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Usher syndrome or retinitis pigmentosa (PMID: 17085681, 24498627, 25324289, 25356976, 26654877, 26667666, 28944237, 29588463; Invitae). 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: 143172). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 17, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -

Retinitis pigmentosa 39 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 24, 2017	- -

Retinal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 15, 2018	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 14, 2015

The p.Thr4337Met variant in USH2A has been previously reported in 5 probands wit h Usher syndrome and 2 probands with retinitis pigmentosa (Aller 2006, McGee 201 0, Besnard 2014, Baux 2014, Lenassi 2015). Two of the probands with Usher syndr ome were compound heterozygotes with a second pathogenic or likely pathogenic va riant, and the two probands with retinitis pigmentosa were both compound heteroz ygous with a second pathogenic variant. This variant has not been identified in large population studies. Computational prediction tools and conservation analy sis do not provide strong support for or against an impact to the protein. In su mmary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic based on multiple reported occur rences with pathogenic USH2A variants in individuals with Usher syndrome. -

Usher syndrome type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Department of Ophthalmology and Visual Sciences Kyoto University

-

- -

Retinitis pigmentosa Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Jul 24, 2023

Clinical significance based on ACMG v2.0 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.49		Loss of glycosylation at T4337 (P = 0.064);
MVP		0.97
MPC		0.24
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.20
gMVP		0.64

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: rs527236137; hg19: chr1-215848243; COSMIC: COSV100241849;