rs143344549

chr1-215648657-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_206933.4(USH2A):c.14453C>T(p.Pro4818Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000669 in 1,614,148 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P4818P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 8.78

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 14 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, 7 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 1-215648657-G-A is Pathogenic according to our data. Variant chr1-215648657-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 504509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215648657-G-A is described in Lovd as [Pathogenic]. Variant chr1-215648657-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.14453C>T	p.Pro4818Leu	missense_variant	66/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.14453C>T	p.Pro4818Leu	missense_variant	66/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.14453C>T	p.Pro4818Leu	missense_variant	66/73

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251372 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000622 AC: 91 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000619 AC XY: 45 AN XY: 727240

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74450

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000805 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2022	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17085681, 22004887, 30081015, 19683999, 20507924, 20591486, 25472526, 29899460, 30245926, 31589614, 34426522, 31980526, 31429209) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4818 of the USH2A protein (p.Pro4818Leu). This variant is present in population databases (rs143344549, gnomAD 0.01%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 17085681, 22004887, 25472526, 29899460). 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: 504509). 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%. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.14453C>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, PM3, PP1-M. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -

Usher syndrome type 2A Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, 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 retinitis pigmentosa 39 (MIM#613809) and type 2A Usher syndrome (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 proline to leucine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 17 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with autosomal recessive retinitis pigmentosa or Usher syndrome (PMIDs: 22004887, 25472526, 29899460, 30081015, 32098976). It has also been reported as likely pathogenic/pathogenic in ClinVar and Deafness Variation Database. (SP) 0905 - No published segregation evidence has been identified for this variant. (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 -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 15, 2023

Variant summary: USH2A c.14453C>T (p.Pro4818Leu) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence, altering a highly conserved residue (HGMD). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 251372 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.14453C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa or Usher Syndrome (Aller_2006, Garcia-Garcia_2011, Huang_2018, Jaijo_2010, Jauregui_2020, Zhao_2015), and several patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven subitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 22, 2016

The p.Pro4818Leu variant in USH2A has been reported in 5 individuals with Usher syndrome and 1 individual with retinitis pigmentosa (Aller 2006, Garcia-Garcia 2 011, Jaijo 2010, McGee 2010, Zhao 2015). Two individuals with Usher syndrome wer e confirmed to have a different truncating variant affecting the other copy of U SH2A. This variant has been identified in several populations by the Exome Aggre gation Consortium with the highest frequency of 3/16510 in South Asian chromosom es (ExAC, http://exac.broadinstitute.org; dbSNP rs143344549). However, this is low enough to be consistent with a recessive carrier frequency. Computational pr ediction tools and conservation analysis suggest that the p.Pro4818Leu variant m ay impact the protein. In summary, although additional studies are required to f ully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Usher syndrome based on its occurrence in trans with another pathogenic variant in USH2A in multiple unrelated affected individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.97
MPC		0.24
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.63

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: rs143344549; hg19: chr1-215821999; COSMIC: COSV104408063;