1-215993095-C-T

Position:

chr1-215993095-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -2 ACMG points: 2P and 4B. PM3_SupportingBS1PP4

This summary comes from the ClinGen Evidence Repository: The c.6730G>A (p.Val2244Met) variant in USH2A is a missense variant predicted to cause a substitution of valine by methionine at amino acid 2244. The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID:27460420) (PM3_Supporting). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID:27460420). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1, PM3_Supporting, PP4; Version 2; 5/15/24). LINK:https://erepo.genome.network/evrepo/ui/classification/CA179542/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:12B:1

Conservation

PhyloP100: 1.67

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.

PM3

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

PP4

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

BS1

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.6730G>A	p.Val2244Met	missense_variant	35/72	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.6730G>A	p.Val2244Met	missense_variant	35/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6730G>A	p.Val2244Met	missense_variant	35/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000506

AC:

127

AN:

251106

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00395

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000228

AC:

333

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00339

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000131

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000577

AC:

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:12Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Usher syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	Dec 31, 2022	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jun 28, 2024	The c.6730G>A (p.Val2244Met) variant in USH2A is a missense variant predicted to cause a substitution of valine by methionine at amino acid 2244. The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID: 27460420) (PM3_Supporting). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID: 27460420). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1, PM3_Supporting, PP4; Version 2; 5/15/24). -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 27, 2018	- -

Usher syndrome type 2A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Oct 26, 2021	A heterozygous missense variation in exon 35 of the USH2A gene that results in the amino acid substitution of Methionine for Valine at codon 2244 was detected. The observed variant c.6730G>A (p.Val2244Met) has a minor allele frequency of 0.1% and 0.006% in the 1000 genomes and gnomAD database respectively. The in silico prediction of the variant are probably damaging by PolyPhen-2 and damaging by SIFT and MutationTaster-2. The reference codon is conserved across species. The segregation analysis showed this variant to be of maternal origin. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 19, 2013

The Val2244Met variant in USH2A has been previously reported in one individual w ith hearing loss; however variants in other genes were also identified in this i ndividual and the authors of the study attributed a homozygous variant in anothe r gene for causing the hearing loss (Shearer 2013). Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of th is variant. -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

This sequence change replaces valine with methionine at codon 2244 of the USH2A protein (p.Val2244Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs550772689, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (Yuya Kobayashi et al). This variant has been observed in an individual affected retinitis pigmentosa (Keren J Carss et al). This variant has been reported to the ClinVar database as Uncertain significance. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val2244Met in USH2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as uncertaiin significance. -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

USH2A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

The USH2A c.6730G>A variant is predicted to result in the amino acid substitution p.Val2244Met. This variant has been reported in individuals with Usher syndrome type 2 (Supplementary Table 4, Bonnet et al. 2016. PubMed ID: 27460420; Table S2, Carss et al 2016. PubMed ID: 28041643). This variant is reported in 0.40% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.2

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.0

REVEL

Benign

0.28

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.36

MutPred

0.39

Loss of catalytic residue at V2244 (P = 0.0648);

MVP

0.69

MPC

0.13

ClinPred

0.28

GERP RS

4.0

Varity_R

0.085

gMVP

0.57

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