rs758571672

chr1-216289392-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_206933.4(USH2A):c.1859G>T(p.Cys620Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8 U:1
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-216289392-C-A is Pathogenic according to our data. Variant chr1-216289392-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 549981.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-216289392-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.1859G>T	p.Cys620Phe	missense_variant	11/72	ENST00000307340.8
USH2A	NM_007123.6	c.1859G>T	p.Cys620Phe	missense_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.1859G>T	p.Cys620Phe	missense_variant	11/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.1859G>T	p.Cys620Phe	missense_variant	11/21	1
USH2A	ENST00000674083.1	c.1859G>T	p.Cys620Phe	missense_variant	11/73

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251316 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43 AN XY: 727112

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: 0.0000747

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Cys620Phe variant in USH2A has been reported in at least 2 individuals with Usher syndrome, including two compound heterozygotes (Le Quesne Stabej 2012). It has also been reported in ClinVar (Variation ID 549981). The p.Cys620Phe variant has been identified in 0.004% (5/129062) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant at the same position, p.Cys620Tyr has been reported in a homozygous individual with Usher syndrome (Baux 2014). In addition, an in vitro functional study suggests that this variant results in a failure of the Usherin peptide to co-immunoprecipitate fibronectin, which may indicate a disruption of normal protein function (Bhattacharya 2005); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PP4, PS3_Supporting. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Oct 24, 2023	The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) in the European(non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID: 22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607*, p.Glu767Serfs*21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID: 36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2023	Variant summary: USH2A c.1859G>T (p.Cys620Phe) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251316 control chromosomes (gnomAD). c.1859G>T has been reported in the literature in multiple individuals affected with Usher Syndrome (examples: Feenstra_2002, Stabej_2012, Molina-Ramirez_2020, Hagag_USH2A_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated this variant abolishes fibronectin/collagen interaction (example: Bhattacharya_2005). The following publications have been ascertained in the context of this evaluation (PMID: 22135276 , 32176120, 31266775, 33089500, 36011334, 16114888). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Oct 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 620 of the USH2A protein (p.Cys620Phe). This variant is present in population databases (rs758571672, gnomAD 0.004%). This missense change has been observed in individuals with Usher syndrome (PMID: 16963483, 22135276; Invitae). ClinVar contains an entry for this variant (Variation ID: 549981). 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 expected to disrupt USH2A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects USH2A function (PMID: 16114888). This variant disrupts the p.Cys620 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 24944099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2023

- -

USH2A-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 23, 2022

The USH2A c.1859G>T variant is predicted to result in the amino acid substitution p.Cys620Phe. This variant has been reported as causative for Usher syndrome (Le Quesne Stabej et al. 2012. PubMed ID: 22135276; Molina-Ramírez et al. 2020. PubMed ID: 32176120). Functional studies have suggested that this variant does not affect collagen binding (Bhattacharya et al. 2004. PubMed ID: 14676276), but abolishes fibronectin binding (Bhattacharya and Cosgrove. 2005. PubMed ID: 16114888). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216462734-C-A). This variant is interpreted as likely pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-9.3	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.95		Loss of methylation at K621 (P = 0.0756);Loss of methylation at K621 (P = 0.0756);
MVP		0.96
MPC		0.27
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.99
gMVP		0.97

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: rs758571672; hg19: chr1-216462734; COSMIC: COSV105883095;