1-215674103-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2_SupportingPM3_StrongPP4

This summary comes from the ClinGen Evidence Repository: The c.13808A>C (p.His4603Pro) variant in USH2A is a missense variant predicted to cause a substitution of histidine by a proline at amino acid 4603. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00000084 (4/1179986 alleles) in the european non-finnish population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.34, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in 1 proband with retinal disease and hearing loss (which was diagnosed at the age of 49 years old) in trans with a pathogenic variant by family testing (PMID:28157192). Besides, this variant has been detected in 4 individuals with USH2A associated conditions which is highly specific for disease (PP4). All individuals were heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.2299del, p.(Glu767Serfs*21); c.5118G>A, p.(Trp1706*); c.2276G>T, p.(Cys759Phe) and c.5573-834A>G; PM3 3 points, Blueprint Genetics internal evidence SCV001239096.1) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A condition (isolated RP) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3_Strong and PP4. (ClinGen Hearing Loss VCEP specifications version 2, 20.11.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA183350/MONDO:0019501/005

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

2
6
11

Clinical Significance

Likely pathogenic reviewed by expert panel P:3U:2

Conservation

PhyloP100: 2.08
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
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
USH2ANM_206933.4 linkc.13808A>C p.His4603Pro 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
USH2AENST00000307340.8 linkc.13808A>C p.His4603Pro missense_variant Exon 63 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.13808A>C p.His4603Pro missense_variant Exon 63 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461772
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Usher syndrome Pathogenic:1
Nov 20, 2024
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Likely pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.13808A>C (p.His4603Pro) variant in USH2A is a missense variant predicted to cause a substitution of histidine by a proline at amino acid 4603. The highest population minor allele frequency in gnomAD v4.1.0 is 0.00000084 (4/1179986 alleles) in the european non-finnish population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.00007) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.34, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in 1 proband with retinal disease and hearing loss (which was diagnosed at the age of 49 years old) in trans with a pathogenic variant by family testing (PMID: 28157192). Besides, this variant has been detected in 4 individuals with USH2A associated conditions which is highly specific for disease (PP4). All individuals were heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.2299del, p.(Glu767Serfs*21); c.5118G>A, p.(Trp1706*); c.2276G>T, p.(Cys759Phe) and c.5573-834A>G; PM3 3 points, Blueprint Genetics internal evidence SCV001239096.1) (PM3_Strong). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive USH2A condition (isolated RP) based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_P, PM3_Strong and PP4. (ClinGen Hearing Loss VCEP specifications version 2, 20.11.2024). -

not provided Pathogenic:1
Feb 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 4603 of the USH2A protein (p.His4603Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 28157192; Invitae). 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: 178937). 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 with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Retinal dystrophy Pathogenic:1
May 23, 2019
Blueprint Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Jul 23, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The His4603Pro variant in USH2A has not been reported in individuals with hearin g loss or in large population studies. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional d ata is needed to determine the clinical significance of this variant. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1
Dec 21, 2017
Counsyl
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
0.35
BayesDel_addAF
Benign
-0.017
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
18
DANN
Benign
0.93
DEOGEN2
Benign
0.23
T
Eigen
Benign
0.18
Eigen_PC
Benign
0.13
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.55
T
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.76
D
MetaSVM
Benign
-0.73
T
MutationAssessor
Uncertain
2.4
M
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.34
Sift
Benign
0.15
T
Sift4G
Uncertain
0.016
D
Polyphen
0.94
P
Vest4
0.53
MutPred
0.61
Gain of glycosylation at H4603 (P = 0.0903);
MVP
0.94
MPC
0.21
ClinPred
0.78
D
GERP RS
2.7
Varity_R
0.86
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs727504551; hg19: chr1-215847445; API