1-216325492-C-T

Variant names:

• chr1-216325492-C-T
• rs121912599
• NM_206933.4:c.956G>A

Variant summary

Our verdict is Pathogenic. Variant got 4 ACMG points: 4P and 0B. PM3 PP1 PP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA252231/MONDO:0019501/005

• 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:11 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 4 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.956G>A	p.Cys319Tyr	missense_variant	Exon 6 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.956G>A	p.Cys319Tyr	missense_variant	Exon 6 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.956G>A	p.Cys319Tyr	missense_variant	Exon 6 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.956G>A	p.Cys319Tyr	missense_variant	Exon 6 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.956G>A	p.Cys319Tyr	missense_variant	Exon 6 of 73			ENSP00000501296.1

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:11 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Usher syndrome type 2A Pathogenic:4

Nov 08, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 30, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 13, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002355 /PMID: 10729113).The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 10729113). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Usher syndrome Pathogenic:2

Aug 03, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Aug 24, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:1 Uncertain:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

May 10, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39 Pathogenic:1

Mar 20, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Nov 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 06, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;