rs143275144

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_206933.4(USH2A):c.14519T>C(p.Leu4840Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000396 in 1,614,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L4840L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:16

Conservation

PhyloP100: 4.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.14519T>C	p.Leu4840Pro	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.14519T>C	p.Leu4840Pro	missense_variant	Exon 66 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.14519T>C	p.Leu4840Pro	missense_variant	Exon 66 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000306

AC:

AN:

251294

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000484

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000402

AC:

588

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000408

AC XY:

297

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000441

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000335

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000471

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Oct 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as homozygous variant in a patient with Usher syndrome, with another variant, C1900G, in cis on both alleles (PMID: 27460420); Observed in the heterozygous state without a second variant in a patient with retinitis pigmentosa in published literature (PMID: 20507924); 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: 24944099, 27460420, 20507924) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4840 of the USH2A protein (p.Leu4840Pro). This variant is present in population databases (rs143275144, gnomAD 0.04%). This missense change has been observed in individual(s) with retinal disease (PMID: 20507924; Invitae). ClinVar contains an entry for this variant (Variation ID: 48442). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 2A

Uncertain:4

Dec 20, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Sep 26, 2019

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Dec 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Leu4840Pro variant in USH2A has been previously reported by our laboratory in 2 individuals with hearing loss who each carried different homozygous pathogenic variants in another gene that explained the hearing loss. This variant has also been reported in 3 individuals with either retinitis pigmentosa or Usher syndrome. It was homozygous in 1 individual, but a variant affecting the remaining copy of USH2A was not identified in the other 2 individuals (McGee 2010, Baux 2014, Bonnet 2016). It has also been identified in 0.05% (59/129026) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID: 48442) .The leucine (Leu) at position 4840 is not highly conserved in mammals and evolutionary distant species, and two mammals (prairie vole and Golden hamster) have a proline (Pro) at the position, supporting that this change at this position may be tolerated. In summary, while the clinical significance of the p.Leu4804Pro variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PM2_Supporting, PP4, PM3_Supporting, BP4. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

May 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing impairment

Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, PP3_Supporting -

Retinitis pigmentosa 39

Uncertain:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Uncertain:1

Aug 06, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.28

MetaRNN

Uncertain

0.63

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.010

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.61

MVP

0.96

MPC

0.10

ClinPred

0.16

GERP RS

5.6

Varity_R

0.59

gMVP

0.80

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