rs35818432

Positions:

• chr1-216292352-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The NM_206933.4(USH2A):​c.1663C>G​(p.Leu555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000972 in 1,613,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00084 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (2 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:9
• Conservation: PhyloP100: 3.10

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_benign. Variant got -4 ACMG points.

• PM1: In a domain Laminin EGF-like 1 (size 56) in uniprot entity USH2A_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_206933.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.035342634).
• BP6: Variant 1-216292352-G-C is Benign according to our data. Variant chr1-216292352-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48472.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=4, Uncertain_significance=6}. Variant chr1-216292352-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.1663C>G	p.Leu555Val	missense_variant	10/72	ENST00000307340.8
USH2A	NM_007123.6	c.1663C>G	p.Leu555Val	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.1663C>G	p.Leu555Val	missense_variant	10/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.1663C>G	p.Leu555Val	missense_variant	10/21	1
USH2A	ENST00000674083.1	c.1663C>G	p.Leu555Val	missense_variant	10/73

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 251082 Hom.: 2 AF XY: 0.00150 AC XY: 203 AN XY: 135706

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000985 AC: 1440 AN: 1461640 Hom.: 2 Cov.: 30 AF XY: 0.00109 AC XY: 792 AN XY: 727128

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00154

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000789

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000969

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74472

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000975

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25262649, 22995991, 14676276, 22004887, 21228398, 11311042, 27884173, 21569298, 29068140, 30245029, 31456290, 32707200) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, 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	Revvity Omics, Revvity	Nov 17, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	USH2A: BP4, BS2 -

Usher syndrome type 2A Uncertain:2 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 02, 2017	p.Leu555Val in exon 10 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified 0.2% (24/10136) of Ashkenazi Jewish c hromosomes and in 0.2% (212/126366) of European chromosomes including 1 homozygo te by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35818432). It has been reported in cis with another pathogenic variant in USH2A (Jaijo 2009, Vozzi 2011). A study has shown that the variant does not i mpact protein function (Bhattacharya 2004). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: USH2A c.1663C>G (p.Leu555Val) results in a conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. 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 0.00097 in 1613940 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00097 vs 0.011), allowing no conclusion about variant significance. c.1663C>G has been reported in the literature in individuals affected with USH2A related conditions without strong evidence for causality (examples: Leory_2001, Colombo_2022, Karali_2022). One publication reported an individual affected with Usher syndrome with this variant and a second pathogenic variant c.1841-2A>G in homozygous state, supporting a benign role for this variant (example: Jaijo_2010). Multiple reports have classified this variant as benign (examples: Shearer_2014 and Azaiez_2018). At least one publication reports experimental evidence that this variant had no effect on usherin/collagen IV binding (example: Bhattacharya_2003). The following publications have been ascertained in the context of this evaluation (PMID: 11311042, 14676276, 19683999, 21569298, 25262649, 30245029, 29068140, 34781295, 36460718). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as benign/likely benign (n=6), VUS (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Retinitis pigmentosa Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The USH2A c.1663C>G 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, BP2. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.035	T;T
MetaSVM	Uncertain	0.024	D
MutationAssessor	Pathogenic	3.6	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.58
MVP		0.88
MPC		0.24
ClinPred		0.13	T
GERP RS		4.8
Varity_R		0.88
gMVP		0.66

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: rs35818432; hg19: chr1-216465694;