rs138398671

Positions:

chr1-215674515-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA143316/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:8

Conservation

PhyloP100: 0.646

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 0 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.13396C>T	p.Pro4466Ser	missense_variant	63/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.13396C>T	p.Pro4466Ser	missense_variant	63/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.13396C>T	p.Pro4466Ser	missense_variant	63/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000216

AC:

AN:

250296

Hom.:

AF XY:

0.000200

AC XY:

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.0000462

Gnomad NFE exome

AF:

0.000435

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000342

AC:

500

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000334

AC XY:

243

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000433

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000250

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000369

Hom.:

Bravo

AF:

0.000215

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000272

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 14, 2021	The p.Pro4466Ser in exon 63 of USH2A has been identified in one individual with retinitis pigmentosa. This individual also carried a large deletion of the USH2A gene (chr1:215836170-215851932) (Carss 2017, PMID: 28041643). It has also been identified in 0.04% (57/128120) of European American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain Significance on Mar 25, 2019 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 48417). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has a lack of conservation of the amino acid position. Of note, chicken has a serine (Ser) at this position despite high nearby amino acid conservation. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 19, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4466 of the USH2A protein (p.Pro4466Ser). This variant is present in population databases (rs138398671, gnomAD 0.05%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 28041643). 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: 48417). 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. 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. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 11, 2024

Variant summary: USH2A c.13396C>T (p.Pro4466Ser) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 250296 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00022 vs 0.011), allowing no conclusion about variant significance. c.13396C>T has been reported in the literature as homozygous or compound heterozygous genotype in two individuals affected with clinical features of Usher Syndrome (Carss_2017, Lin_2024)). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28041643, 38219857). ClinVar contains an entry for this variant (Variation ID: 48417). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Usher syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Nov 22, 2022

The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 30, 2018

- -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 06, 2019

- -

USH2A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

The USH2A c.13396C>T variant is predicted to result in the amino acid substitution p.Pro4466Ser. This variant was reported, along with a large deletion in the same gene, in an individual with retinitis pigmentosa (Table S2, Carss et al. 2017. PubMed ID: 28041643). This variant was also described in the homozygous state in an individual with retinal disease (Turro et al. 2020. PubMed ID: 32581362). This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.086

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.084

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.8

REVEL

Benign

0.049

Sift

Benign

0.61

Sift4G

Benign

0.93

Polyphen

0.045

Vest4

0.072

MVP

0.82

MPC

0.037

ClinPred

0.028

GERP RS

1.2

Varity_R

0.060

gMVP

0.34

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