rs1423536179

Positions:

• chr1-216323634-G-A
• chr1-216323634-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_206933.4(USH2A):​c.1390C>T​(p.Arg464Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,390 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R464H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.72

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 11 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 107 pathogenic changes around while only 17 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 chr1-216323633-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 636117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 1-216323634-G-A is Pathogenic according to our data. Variant chr1-216323634-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551303.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=2, Uncertain_significance=2}. Variant chr1-216323634-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.1390C>T	p.Arg464Cys	missense_variant	8/72	ENST00000307340.8
USH2A	NM_007123.6	c.1390C>T	p.Arg464Cys	missense_variant	8/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.1390C>T	p.Arg464Cys	missense_variant	8/72	1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.1390C>T	p.Arg464Cys	missense_variant	8/21	1
USH2A	ENST00000674083.1	c.1390C>T	p.Arg464Cys	missense_variant	8/73

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250700 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135464

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461390 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727000

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinal dystrophy Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 30, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 26, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 464 of the USH2A protein (p.Arg464Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (PMID: 28559085, 32531858; Invitae). ClinVar contains an entry for this variant (Variation ID: 551303). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Arg464 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28157192, 30718709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 11, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.7	H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.88		Loss of disorder (P = 0.0306);Loss of disorder (P = 0.0306);
MVP		0.96
MPC		0.26
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.61
gMVP		0.79

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: rs1423536179; hg19: chr1-216496976; COSMIC: COSV56334150;