rs149553844

chr1-215993155-C-Achr1-215993155-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP5_Strong

The NM_206933.4(USH2A):c.6670G>T(p.Gly2224Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,614,054 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:13
• Conservation: PhyloP100: 3.57

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 1-215993155-C-A is Pathogenic according to our data. Variant chr1-215993155-C-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 209202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=10, Pathogenic=1}. Variant chr1-215993155-C-A is described in Lovd as [Likely_pathogenic]. Variant chr1-215993155-C-A is described in Lovd as [Pathogenic]. Variant chr1-215993155-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.6670G>T	p.Gly2224Cys	missense_variant	35/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.6670G>T	p.Gly2224Cys	missense_variant	35/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.6670G>T	p.Gly2224Cys	missense_variant	35/73

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000454 AC: 114 AN: 251048 Hom.: 0 AF XY: 0.000413 AC XY: 56 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.000652

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000486 AC: 710 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 362 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.000538

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74450

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000379 AC: 46

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 28, 2022	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2224 of the USH2A protein (p.Gly2224Cys). This variant is present in population databases (rs149553844, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with USH2A-related retinopathy (PMID: 25412400, 27160483, 28041643). ClinVar contains an entry for this variant (Variation ID: 209202). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Observed in an individual who underwent genetic testing for retinal dystrophy who also possessed other variants in USH2A (Carss et al., 2017; Khan et al., 2017; Zampaglione et al., 2020); however, segregation analysis was not performed; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25412400, 26633545, 32037395, 28041643, 36785559, 32531858, 27160483, 35266249) -

Usher syndrome type 2A Pathogenic:1 Uncertain:1

Pathogenic, flagged submission	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Retinitis pigmentosa Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Uncertain significance, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -

Retinitis pigmentosa 39 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 10, 2013	This variant was found once in our laboratory with a pathogenic variant [E767fs] and another missense variant [E3448K; phase undetermined] in a 32-year-old female with retinitis pigmentosa. Variant possibly pathogenic in recessive state; heterozygotes would be carriers. -
Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.6670G>T 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, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 20, 2023

Variant summary: USH2A c.6670G>T (p.Gly2224Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00045 vs 0.011), allowing no conclusion about variant significance. c.6670G>T has been reported in the literature in individuals affected with inherited retinal disease, without strong evidence for causality (Khan_2016, Carss_2017, Jiman_2020, etc). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters classified the variant as VUS while two classified as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 09, 2018

- -

USH2A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

The USH2A c.6670G>T variant is predicted to result in the amino acid substitution p.Gly2224Cys. This variant was previously reported in the heterozygous state in at least three patients with autosomal recessive retinitis pigmentosa (Table S7, Consugar et al. 2015. PubMed ID: 25412400; Table S2, Carss et al. 2016. PubMed ID: 28041643; Khan et al. 2017. PubMed ID: 27160483; Table S2, Zampaglione et al. 2020. PubMed ID: 32037395). In all of these patients a second missense variant (p.Glu3448Lys) was also present, while in two of the patients a third truncating variant was also present. In one additional patient with RP this variant was in reported in a patient along with a truncating variant in the absence of the p.Glu3448Lys variant (Table S1, Weisschuh et al. 2020. PubMed ID: 32531858). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216166497-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MVP		0.96
MPC		0.24
ClinPred		0.34	T
GERP RS		4.3
Varity_R		0.35
gMVP		0.65

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: rs149553844; hg19: chr1-216166497;