rs201709513

chr1-216196698-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_206933.4(USH2A):c.4106C>T(p.Ser1369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1369S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:4
• Conservation: PhyloP100: 1.74

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-216196698-G-A is Pathogenic according to our data. Variant chr1-216196698-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48511.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Uncertain_significance=4, Pathogenic=2}. Variant chr1-216196698-G-A is described in Lovd as [Pathogenic]. Variant chr1-216196698-G-A is described in Lovd as [Pathogenic]. Variant chr1-216196698-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.4106C>T	p.Ser1369Leu	missense_variant	19/72	ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+773G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.4106C>T	p.Ser1369Leu	missense_variant	19/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.4106C>T	p.Ser1369Leu	missense_variant	19/21	1
USH2A-AS1	ENST00000420867.1	n.362+773G>A		intron_variant, non_coding_transcript_variant		3
USH2A	ENST00000674083.1	c.4106C>T	p.Ser1369Leu	missense_variant	19/73

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 250578 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135416

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000306 AC: 447 AN: 1461008 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 726826

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000359

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74306

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1369 of the USH2A protein (p.Ser1369Leu). This variant is present in population databases (rs201709513, gnomAD 0.08%). This missense change has been observed in individual(s) with USH2A-related disease (PMID: 20591486, 24154662, 26927203, 27957503, 31047384; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48511). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	USH2A: PM2, PP1, BP4 -

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.4106C>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: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DBGen Ocular Genomics	Jun 23, 2021	- -

Usher syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 21, 2022

Variant summary: USH2A c.4106C>T (p.Ser1369Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250578 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00016 vs 0.011), allowing no conclusion about variant significance. c.4106C>T has been reported in the literature in individuals affected with features of Usher Syndrome and with retinitis pigmentosa (RP) (e.g. Cremers_2007, Zhao_2015, Dad_2016). Furthermore, the variant was shown to co-segregate with retinitis pigmentosa in siblings from two different families (Wang_2014, Comander_2017). At-least one putative "in cis" co-occurrence of the variant with either of two other pathogenic variants (c.9270C>A, p.C3090X or c.6159delA, p.E2054KfsX10; phase unknown) has been reported in one RP patient (Wang_2014), while in another instance following internal testing the variant was reported in cis (confirmed via parental studies) with a pathogenic variant (c.6159delA, p.E2054KfsX10) in one individual. These data indicate that the variant is likely to be associated with disease. 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. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; Pathogenic/Likely pathogenic, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Usher syndrome type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 22, 2023

Criteria applied: PM3_VSTR,PM1,PM2_SUP; Identified as compund heterozygous with NM_206933.4:c.2299del -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 16, 2019

- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Apr 01, 2021

The p.Ser1369Leu variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 25, 2016

The p.Ser1369Leu variant in USH2A has been previously reported in three individu als with Usher syndrome, one individual with retinitis pigmentosa, and one indiv idual with hearing loss (Colombo 2015, Cremers 2007, Dad 2015, Wang 2014, LMM da ta). In the proband with retinitis pigmentosa, a second variant of uncertain si gnificance was identified and the two variants segregated in an affected sibling ; however, cis/trans testing was not performed (Wang 2014). In the remaining pr obands, a pathogenic variant affecting the remaining copy of USH2A was not ident ified. This variant has been identified in 13/65610 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201 709513); however, this frequency is not high enough to rule out a pathogenic rol e. The serine (Ser) at position 1369 is not conserved through species, with 2 m ammals (squirrel and brush-tailed rat) and 2 bird species having a leucine, sugg esting that this change may be tolerated. Additional computational prediction t ools do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser1369Leu variant is uncertain. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.23
Sift	Benign	0.50	T;T
Sift4G	Benign	0.065	T;T
Polyphen		0.035	B;B
Vest4		0.71
MVP		0.91
MPC		0.030
ClinPred		0.041	T
GERP RS		3.1
Varity_R		0.063
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201709513; hg19: chr1-216370040; COSMIC: COSV56353817; COSMIC: COSV56353817;