rs143344549

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_206933.4(USH2A):c.14453C>T(p.Pro4818Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,148 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P4818P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 8.78

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

PP5

Variant 1-215648657-G-A is Pathogenic according to our data. Variant chr1-215648657-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215648657-G-A is described in Lovd as [Pathogenic]. Variant chr1-215648657-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.14453C>T	p.Pro4818Leu	missense_variant	Exon 66 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.14453C>T	p.Pro4818Leu	missense_variant	Exon 66 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.14453C>T	p.Pro4818Leu	missense_variant	Exon 66 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

251372

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000622

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000486

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000112

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000805

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Pathogenic:4

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinitis pigmentosa 39 (MIM#613809) and type 2A Usher syndrome (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with autosomal recessive retinitis pigmentosa or Usher syndrome (PMIDs: 22004887, 25472526, 29899460, 30081015, 32098976). It has also been reported as likely pathogenic/pathogenic in ClinVar and Deafness Variation Database. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:3

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4818 of the USH2A protein (p.Pro4818Leu). This variant is present in population databases (rs143344549, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17085681, 22004887, 25472526, 29899460). 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: 504509). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jun 17, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 37322672, 31964843, 17085681, 30081015, 19683999, 20507924, 20591486, 25472526, 29899460, 30245926, 31589614, 34426522, 31980526, 31429209, 22004887) -

Retinitis pigmentosa 39

Pathogenic:3

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The USH2A c.14453C>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, PM3, PP1-M. Based on this evidence we have classified this variant as Likely Pathogenic. -

Mar 12, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome

Pathogenic:1

Feb 15, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.14453C>T (p.Pro4818Leu) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence, altering a highly conserved residue (HGMD). 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 6.4e-05 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.14453C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Usher Syndrome (Aller_2006, Garcia-Garcia_2011, Huang_2018, Jaijo_2010, Jauregui_2020, Zhao_2015), and several patients were reported as compound heterozygous with other (likely) pathogenic variants. 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. Seven subitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness

Pathogenic:1

Dec 22, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, Jaijo 2010, McGee 2010, Zhao 2015). Two individuals with Usher syndrome wer e confirmed to have a different truncating variant affecting the other copy of U SH2A. This variant has been identified in several populations by the Exome Aggre gation Consortium with the highest frequency of 3/16510 in South Asian chromosom es (ExAC, http://exac.broadinstitute.org; dbSNP rs143344549). However, this is low enough to be consistent with a recessive carrier frequency. Computational pr ediction tools and conservation analysis suggest that the p.Pro4818Leu variant m ay impact the protein. In summary, although additional studies are required to f ully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome based on its occurrence in trans with another pathogenic variant in USH2A in multiple unrelated affected individuals. -

Retinal dystrophy

Pathogenic:1

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

USH2A-related disorder

Pathogenic:1

Aug 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The USH2A c.14453C>T variant is predicted to result in the amino acid substitution p.Pro4818Leu. This variant has been reported in the compound heterozygous state with a protein-truncating variant in patients who presented with Usher syndrome or retinitis pigmentosa (see for example, family FRP35, Aller et al. 2006. PubMed ID: 17085681; patient RP107, Table 2, Zhao et al. 2015. PubMed ID: 25472526; patient RP690M, Table 2, Garcia-Garcia et al. 2011. PubMed ID: 22004887). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.080

MutationAssessor

Pathogenic

3.1

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.51

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MVP

0.97

MPC

0.24

ClinPred

0.88

GERP RS

5.6

Varity_R

0.23

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over