1-216200031-C-T

Variant names:

• chr1-216200031-C-T
• rs483353055
• NM_206933.4:c.3407G>A

Variant summary

Our verdict is Pathogenic. Variant got 4 ACMG points: 4P and 0B. PM3 PM2_Supporting PP4

This summary comes from the ClinGen Evidence Repository: The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID:22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA269917/MONDO:0019501/005

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 4.84

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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 4 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
USH2A	NM_206933.4	c.3407G>A	p.Ser1136Asn	missense_variant	Exon 17 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.3407G>A	p.Ser1136Asn	missense_variant	Exon 17 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.3407G>A	p.Ser1136Asn	missense_variant	Exon 17 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.3407G>A	p.Ser1136Asn	missense_variant	Exon 17 of 73			ENSP00000501296.1
USH2A-AS1	ENST00000420867.1	n.363-3999C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727216

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome type 2A Pathogenic:2 Uncertain:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibronectin type-III 1 domain (PDB). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. A missense variant (p.Ser1136Arg) of greater Grantham score has been reported as both a VUS and likely pathogenic, and was identified in a patient with congenital hearing loss, and their affected sibling (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic in multiple patients with Usher syndrome, inherited retinal disease and retinitis pigmentosa (ClinVar, PMID: 30718709,PMID: 28512305, PMID: 27208204, PMID: 25991456, PMID: 27957503, PMID: 27460420). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant was reported in two members of family with Usher syndrome, with unknown relation (PMID: 27957503). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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Molecular Genetics Laboratory; Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 01, 2019

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome Pathogenic:1

Sep 26, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.3407G>A variant in USH2A is a missense variant predicted to cause substitution of serine to asparagine at amino acid 1136. This variant is absent from large population studies (PM2_Supporting, gnomAD v2.1.1). The computational predictor REVEL gives a score of 0.466 which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been reported in at least 6 probands with USH2A-related disorders, including four individuals with autosomal recessive Usher syndrome and two individuals with isolated retinopathy. Of these individuals, the variant was confirmed in trans with a pathogenic variant in two individuals, but phase with a second pathogenic variant was unclear in the remaining 4 individuals (PM3_VeryStrong; PMID: 22135276, 25991456, 27957503, 36011334). Of note, the two individuals with isolated retinopathy harbored the pathogenic p.Cys759Phe variant, which is commonly found in individuals with an isolated retinopathy phenotype (SCV001334331.1). At least one patient with this variant was diagnosed with Usher syndrome (PP4). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive USH2A-related disorders including Usher syndrome and isolated retinopathy based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PM3_VeryStrong, PP4. (The ClinGen Hearing Loss VCEP Specifications Version 2; 09/26/2022) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1

Apr 18, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1136 of the USH2A protein (p.Ser1136Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Usher syndrome, retinitis pigmentosa, or cone-rod dystrophy (PMID: 22135276, 25991456, 27460420, 27957503, 28512305, 30718709). 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: 133312). 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 expected to disrupt USH2A protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1136 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.71	T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.6	H;H
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.66		Loss of disorder (P = 0.105);Loss of disorder (P = 0.105);
MVP		0.93
MPC		0.22
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.52
gMVP		0.73

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

Other links and lift over

dbSNP: rs483353055; hg19: chr1-216373373;