1-216325594-A-G

Position:

• chr1-216325594-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_206933.4(USH2A):​c.854T>C​(p.Ile285Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 5.72

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 67 pathogenic changes around while only 10 benign (87%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.854T>C	p.Ile285Thr	missense_variant	6/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.854T>C	p.Ile285Thr	missense_variant	6/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.854T>C	p.Ile285Thr	missense_variant	6/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.854T>C	p.Ile285Thr	missense_variant	6/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.854T>C	p.Ile285Thr	missense_variant	6/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 17, 2011	Variant classified as Uncertain Significance - Favor Pathogenic. The Ile285Thr v ariant in USH2A has not been reported in the literature nor previously identifie d by our laboratory. Computational analyses (biochemical amino acid properties, homology, PolyPhen2, SIFT, AlignGVGD) do not provide strong support for or again st pathogenicity. In summary, the clinical significance of this variant cannot b e determined with certainty at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2024	Variant summary: USH2A c.854T>C (p.Ile285Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.854T>C has been reported in the literature in individuals affected with Usher Syndrome (e.g. Lenassi_2015, Bonnet_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25649381, 27460420, 36460718). ClinVar contains an entry for this variant (Variation ID: 48603). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jul 07, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 285 of the USH2A protein (p.Ile285Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa and/or Usher syndrome (PMID: 25649381, 27460420; Invitae). ClinVar contains an entry for this variant (Variation ID: 48603). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Retinitis pigmentosa 39 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Usher syndrome type 2A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.62		Loss of stability (P = 0.023);Loss of stability (P = 0.023);
MVP		0.89
MPC		0.060
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.23
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397518038; hg19: chr1-216498936;