1-216325492-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_206933.4(USH2A):c.956G>A(p.Cys319Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,622 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C319F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9 U:1
• Conservation: PhyloP100: 7.52

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 18 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 107 pathogenic changes around while only 18 benign (86%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-216325492-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2503086.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-216325492-C-T is Pathogenic according to our data. Variant chr1-216325492-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2355.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-216325492-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.956G>A	p.Cys319Tyr	missense_variant	6/72	ENST00000307340.8
USH2A	NM_007123.6	c.956G>A	p.Cys319Tyr	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.956G>A	p.Cys319Tyr	missense_variant	6/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.956G>A	p.Cys319Tyr	missense_variant	6/21	1
USH2A	ENST00000674083.1	c.956G>A	p.Cys319Tyr	missense_variant	6/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000598 AC: 15 AN: 250870 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000435

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461622 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000358

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome type 2A Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2000	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 30, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_206933.2(USH2A):c.956G>A(C319Y) is a missense variant classified as likely pathogenic in the context of USH2A-related disorders. C319Y has been observed in cases with relevant disease (PMID: 10729113, 26969326, 33089500). Functional assessments of this variant are not available in the literature. C319Y has been observed in population frequency databases (gnomAD: AMR 0.04%). In summary, NM_206933.2(USH2A):c.956G>A(C319Y) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Usher syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2021	Variant summary: USH2A c.956G>A (p.Cys319Tyr) results in a non-conservative amino acid change in 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 6e-05 in 250870 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (6e-05 vs 0.011), allowing no conclusion about variant significance. c.956G>A has been reported in the literature in individuals affected with Usher Syndrome or hearing loss (Weston_2000, Cremers_2007, Sloan-Heggen_2016, Wafa_2021). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=1, likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Aug 03, 2022	The c.956G>A variant in USH2A is a missense variant predicted to cause substitution of cysteine by tyrosine at amino acid 319. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002679 (15/34508 alleles) in the Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.524, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. At least one patient was homozygous for this variant and displayed moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, which is highly specific for Usher syndrome (PP4, PMID:10729113). This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID: 26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong). One of the individuals who was compound heterozygous for the variant and another pathogenic variant in USH2A (RCV000599950.1), had an affected sibling in whom both variants segregated (PP1). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP4, PM3_VS, PP1 (Hearing Loss VCEP specifications version 2; 6/15/2022). -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 319 of the USH2A protein (p.Cys319Tyr). This variant is present in population databases (rs121912599, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Usher syndrome and/or inherited retinal dystrophy (PMID: 10729113, 26969326; Invitae). 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: 2355). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2016	- -

Retinitis pigmentosa 39 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2023

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 01, 2017

The p.Cys319Tyr variant in USH2A has been reported in 2 individuals with Usher s yndrome (Weston 2000, Sloan-Heggen 2016), and one infant with mild to moderate h earing loss and segregated in an affected sibling (LMM data). One of these indiv iduals was homozygous, and two were compound heterozygous with a second likely p athogenic USH2A variant. This variant has been identified in 0.04% (15/33496) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.br oadinstitute.org/; dbSNP rs121912599) and has also been reported in ClinVar (Var iation ID: 2355). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency . Computational prediction tools and conservation analyses suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity on its own. In summary, although additional studies ar e required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP3, PM3_Supporting. -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.99		Gain of phosphorylation at C319 (P = 0.0502);Gain of phosphorylation at C319 (P = 0.0502);
MVP		0.92
MPC		0.28
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98

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: rs121912599; hg19: chr1-216498834;