rs142898216

chr1-216247062-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_206933.4(USH2A):c.2332G>T(p.Asp778Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,613,902 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D778D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 4.59

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Laminin EGF-like 5 (size 47) in uniprot entity USH2A_HUMAN there are 20 pathogenic changes around while only 2 benign (91%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 1-216247062-C-A is Pathogenic according to our data. Variant chr1-216247062-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178583.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=4}. Variant chr1-216247062-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.2332G>T	p.Asp778Tyr	missense_variant	13/72	ENST00000307340.8
USH2A	NM_007123.6	c.2332G>T	p.Asp778Tyr	missense_variant	13/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.2332G>T	p.Asp778Tyr	missense_variant	13/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.2332G>T	p.Asp778Tyr	missense_variant	13/21	1
USH2A	ENST00000674083.1	c.2332G>T	p.Asp778Tyr	missense_variant	13/73

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250894 Hom.: 1 AF XY: 0.0000295 AC XY: 4 AN XY: 135554

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000868

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461788 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727202

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74304

Gnomad4 AFR AF: 0.000435

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 778 of the USH2A protein (p.Asp778Tyr). This variant is present in population databases (rs142898216, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326; 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: 178583). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2021	The USH2A c.2332G>T; p.Asp778Tyr variant (rs142898216; ClinVar Variation ID: 178583) has been previously observed in patients with clinical features of Usher syndrome (US) or retinitis pigmentosa (RP). One patient with US found to be homozygous for this variant, while one US and one RP patient were found to carry this variant in a presumed transheterozygous configuration with other established pathogenic variants in USH2A (Aller 2006, Lenassi 2015, Sloan-Heggen 2016). This variants is rare in the general population, though it is found at higher frequencies is African Americans in in the Genome Aggregation Database (0.056% MAF; 14 out of 24,968 chromosomes, including 1 homozygous individual). The aspartic acid at codon 778 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.598). Based on the available information, the clinical significance of this variant is uncertain. References: Aller et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006 Nov;43(11):e55. PMID: 17085681 Lenassi et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27. PMID: 25649381 Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450. PMID: 26969326 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 14, 2021

Variant summary: USH2A c.2332G>T (p.Asp778Tyr) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250894 control chromosomes in the gnomAD database, including 1 homozygote. c.2332G>T has been reported in the literature in multiple compound heterozygous individuals affected with Usher Syndrome or retinal disease (examples: Aller_2006, Sloan-Heggen_2016, Zenteno_2019, and McGowan_2020), as well as a homozygous individual with normal hearing and nyctalopia (Lenassi_2015). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and as a variant of uncertain significance (n=1). 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

Sep 26, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 07, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp778Tyr variant in USH2A has been reported in 1 Spanish individual with Usher syndrome who also carried a known pathogenic variant (Aller 2006). This variant has been identified in 0.05% (2/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs142898216); howev er this frequency is not high enough to rule out a pathogenic role. Computationa l prediction tools suggest that the p.Asp778Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of the p.Asp778Tyr variant is uncertain. -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 03, 2021

NM_206933.2(USH2A):c.2332G>T(D778Y) is a missense variant classified as a variant of uncertain significance in the context of USH2A-related disorders. D778Y has been observed in cases with relevant disease (PMID: 31736247, 25649381, 17085681, 26969326). Functional assessments of this variant are not available in the literature. D778Y has been observed in population frequency databases (gnomAD: AFR 0.05%). In summary, there is insufficient evidence to classify NM_206933.2(USH2A):c.2332G>T(D778Y) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.96
MVP		0.97
MPC		0.25
ClinPred		0.84	D
GERP RS		6.1
Varity_R		0.67
gMVP		0.93

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: rs142898216; hg19: chr1-216420404;