chr1-215650648-C-T

Variant names:

• chr1-215650648-C-T
• rs397517990
• NM_206933.4:c.14287G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_206933.4(USH2A):​c.14287G>A​(p.Gly4763Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,884 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4763E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 7.88
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_206933.4 (USH2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 9 uncertain in NM_206933.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-215650647-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1047575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 1-215650648-C-T is Pathogenic according to our data. Variant chr1-215650648-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 48433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.14287G>A	p.Gly4763Arg	missense_variant	Exon 65 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.14287G>A	p.Gly4763Arg	missense_variant	Exon 65 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.14287G>A	p.Gly4763Arg	missense_variant	Exon 65 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 39 Pathogenic:3

Mar 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Another variant with the same amino acid change has been classified as pathogenic/likely pathogenic (PS1, p.Gly4763Arg). Variant is located in a mutational hotspot where >50% of variants are pathogenic (PM1). Variant is not found in gnomAD genomes and homozygous allele count in gnomAD exomes is less than 0 (PM2). Other variants at this amino acid residue have been classified as pathogenic/likely pathogenic (PM5, p.Gly4763Glu; p.Gly4763Val) -

Usher syndrome type 2A Pathogenic:2

Oct 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3. -

Nov 04, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 09, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4763 of the USH2A protein (p.Gly4763Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Usher syndrome (PMID: 25649381, 27460420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48433). 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. -

Rare genetic deafness Pathogenic:1

Sep 27, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gly4763Arg variant in USH2A has been reported in an individual with Usher sy ndrome and in an individual with nonsyndromic retinitis pigmentosa (McGee 2010). In addition, this residue is conserved in mammals. Furthermore, we have identif ied the Gly4763Arg variant in combination with a pathogenic USH2A variant in two siblings with Usher syndrome. In summary, this variant is likely to be pathogen ic. -

Retinal dystrophy Uncertain:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.0023	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		7.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.56		Gain of MoRF binding (P = 0.0184);
MVP		0.97
MPC		0.25
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.44
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397517990; hg19: chr1-215823990; COSMIC: COSV56359977;