rs371777049

chr1-216325540-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_206933.4(USH2A):c.908G>A(p.Arg303His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R303C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 2.74

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 14 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 107 pathogenic changes around while only 18 benign (86%) 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 chr1-216325541-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1441479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-216325540-C-T is Pathogenic according to our data. Variant chr1-216325540-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216325540-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-216325540-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-216325540-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.908G>A	p.Arg303His	missense_variant	6/72	ENST00000307340.8
USH2A	NM_007123.6	c.908G>A	p.Arg303His	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.908G>A	p.Arg303His	missense_variant	6/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.908G>A	p.Arg303His	missense_variant	6/21	1
USH2A	ENST00000674083.1	c.908G>A	p.Arg303His	missense_variant	6/73

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250388 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.0000620

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461328 Hom.: 0 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 726960

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000549

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74206

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000594

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 303 of the USH2A protein (p.Arg303His). This variant is present in population databases (rs371777049, gnomAD 0.006%). This missense change has been observed in individual(s) with Usher syndrome and retinitis pigmentosa (PMID: 19881469, 25342620, 28157192). 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: 284411). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. This variant disrupts the p.Arg303 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 14970843, 28157192), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24944099, 25342620, 22004887, 21569298, 28157192, 31766479, 30872814, 19881469) -

Retinitis pigmentosa 39 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 05, 2022	This variant was identified as homozygous._x000D_ Criteria applied: PM3_STR, PM5, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 12, 2017	- -

Hearing impairment Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, no assertion criteria provided	research	Center for Statistical Genetics, Columbia University	Oct 08, 2018	- -

Usher syndrome type 2A Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 09, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 27, 2022

Variant summary: USH2A c.908G>A (p.Arg303His) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250388 control chromosomes. c.908G>A has been reported in the literature in multiple individuals affected with Usher Syndrome (example, Sanchez-Alcudia_2014, Weisschuh_2020, Schrauwen_2019, Bonnet_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 02, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.33
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.032	D;D
Polyphen		1.0	D;D
Vest4		0.73
MVP		0.91
MPC		0.098
ClinPred		0.88	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.86

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: rs371777049; hg19: chr1-216498882;