rs745693690

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM3PP4

This summary comes from the ClinGen Evidence Repository: The c.13217T>C variant in USH2A is a missense variant predicted to cause substitution of leucine by proline at amino acid 4406 (p.Leu4406Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.02% (15/74934) in the African / African American population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.338, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been identified in one individual with Usher syndrome who was compound heterozygous with a pathogenic variant phase unknown (PP4, 0.5 point PM3; PMID:36011402). This individual also had a third variant that was reviewed by the Hearing Loss VCEP and was determined to be likely benign. This variant was also identified in an individual with retinitis pigmentosa who was compound heterozygous with a pathogenic variant, though phase was unknown (0.5 point PM3, PMID:37217489). The variant was also reported in other individuals with Usher syndrome; however, these individuals were not awarded any evidence as zygosity / phasing was unknown, the second variant was likely benign, or the individual had a possible alternate explanation for disease (PMID:26927203, 24944099, 36011402). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1393328/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:8

Conservation

PhyloP100: 1.06

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.13217T>C	p.Leu4406Pro	missense_variant	Exon 63 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.13217T>C	p.Leu4406Pro	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.13217T>C	p.Leu4406Pro	missense_variant	Exon 63 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250910

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000616

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000659

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:1Uncertain:2

Nov 20, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.13217T>C variant in USH2A is a missense variant predicted to cause substitution of leucine by proline at amino acid 4406 (p.Leu4406Pro). The highest population minor allele frequency in gnomAD v4.1.0 is 0.02% (15/74934) in the African / African American population (PM2_supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.338, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been identified in one individual with Usher syndrome who was compound heterozygous with a pathogenic variant phase unknown (PP4, 0.5 point PM3; PMID: 36011402). This individual also had a third variant that was reviewed by the Hearing Loss VCEP and was determined to be likely benign. This variant was also identified in an individual with retinitis pigmentosa who was compound heterozygous with a pathogenic variant, though phase was unknown (0.5 point PM3, PMID: 37217489). The variant was also reported in other individuals with Usher syndrome; however, these individuals were not awarded any evidence as zygosity / phasing was unknown, the second variant was likely benign, or the individual had a possible alternate explanation for disease (PMID: 26927203, 24944099, 36011402). In summary, this variant has been classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024). -

Jun 06, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH2A c.13217T>C (p.Leu4406Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 8e-06 in 250910 control chromosomes. c.13217T>C has been observed in individual(s) affected with Usher Syndrome or Retinitis Pigmentosa (Baux_2014, Pierrache_2016, internal data). These data indicate that the variant is likely to 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: 24944099, 26927203). ClinVar contains an entry for this variant (Variation ID: 556334). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

May 01, 2024

Laboratory of Human Genetics, Universidade de São Paulo

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A:NM_206933.2:c.13217T>C has extremely low frequency in gnomAD population databases, it is associated with a recessive disorder, detected in trans with a pathogenic variant, in affected cases (PM3). Here it was found with c.12100G>T in one affected individual with Usher syndrome, with three additional untested siblings, born from unaffected unrelated couple. -

not provided

Pathogenic:1Uncertain:1

Oct 01, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24944099, 37217489, 36011402) -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

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 4406 of the USH2A protein (p.Leu4406Pro). This variant is present in population databases (rs745693690, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099, 26927203; internal data). 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: 556334). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A

Uncertain:2

Jan 28, 2021

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 21, 2023

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Jan 24, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Retinitis pigmentosa 39

Uncertain:1

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A c.13217T>C 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. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Retinal dystrophy

Uncertain:1

May 31, 2017

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

Uncertain

0.49

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.8

PhyloP100

1.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.34

Sift

Benign

0.17

Sift4G

Benign

0.21

Polyphen

0.93

Vest4

0.49

MutPred

0.65

Loss of catalytic residue at L4406 (P = 0.0447);

MVP

0.87

MPC

0.13

ClinPred

0.20

GERP RS

1.1

Varity_R

0.82

gMVP

0.72

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over