rs1230923403

Positions:

• chr1-216190312-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_206933.4(USH2A):​c.4307C>T​(p.Pro1436Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,416 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 8.48

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Fibronectin type-III 4 (size 104) in uniprot entity USH2A_HUMAN there are 33 pathogenic changes around while only 6 benign (85%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4307C>T	p.Pro1436Leu	missense_variant	20/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4307C>T	p.Pro1436Leu	missense_variant	20/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4307C>T	p.Pro1436Leu	missense_variant	20/72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.4307C>T	p.Pro1436Leu	missense_variant	20/21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.4307C>T	p.Pro1436Leu	missense_variant	20/73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250612 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135456

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

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: 0.00000137 AC: 2 AN: 1460416 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726542

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25356976, 31964843) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 553700). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25356976). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1436 of the USH2A protein (p.Pro1436Leu). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 17, 2022

Variant summary: USH2A c.4307C>T (p.Pro1436Leu) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250612 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4307C>T has been reported in the literature in at least one individual affected with inherited retinal dystrophy (Huang_2014). The data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.87		Loss of methylation at K1435 (P = 0.0666);Loss of methylation at K1435 (P = 0.0666);
MVP		0.97
MPC		0.24
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.34
gMVP		0.73

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: rs1230923403; hg19: chr1-216363654;