rs138398671

Variant names:

• chr1-215674515-G-A
• rs138398671
• NM_206933.4:c.13396C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA143316/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:8
• Conservation: PhyloP100: 0.646

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 0 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.13396C>T	p.Pro4466Ser	missense_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.13396C>T	p.Pro4466Ser	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.13396C>T	p.Pro4466Ser	missense_variant	Exon 63 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000216 AC: 54 AN: 250296 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135252

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000342 AC: 500 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.000334 AC XY: 243 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74336

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000369 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4466 of the USH2A protein (p.Pro4466Ser). This variant is present in population databases (rs138398671, gnomAD 0.05%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 28041643). 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: 48417). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. 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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro4466Ser in exon 63 of USH2A has been identified in one individual with retinitis pigmentosa. This individual also carried a large deletion of the USH2A gene (chr1:215836170-215851932) (Carss 2017, PMID: 28041643). It has also been identified in 0.04% (57/128120) of European American chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Uncertain Significance on Mar 25, 2019 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 48417). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has a lack of conservation of the amino acid position. Of note, chicken has a serine (Ser) at this position despite high nearby amino acid conservation. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3_Supporting, BP4. -

Retinitis pigmentosa Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Uncertain:1

Jul 11, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.13396C>T (p.Pro4466Ser) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 250296 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00022 vs 0.011), allowing no conclusion about variant significance. c.13396C>T has been reported in the literature as homozygous or compound heterozygous genotype in two individuals affected with clinical features of Usher Syndrome (Carss_2017, Lin_2024)). 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: 28041643, 38219857). ClinVar contains an entry for this variant (Variation ID: 48417). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Usher syndrome Uncertain:1

Nov 22, 2022

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_206933.4:c.13396C>T in USH2A is a missense variant predicted to cause substitution of proline by serine at amino acid 4466 (p.Pro4466Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00044 (57/128120 alleles) in the European (non-Finnish) population, which does not meet either PM2_supporting nor BS1 criteria. The REVEL computational prediction analysis tool produced a score of 0.049, which is below the threshold necessary to apply BP4. This variant has been reported in two probands, one with retinitis pigmentosa, however the second variant was not specified and no PM3 points were awarded and the other homozygous with inherited retinal disease (PM3_Supporting; PMID 28041643, 32581362). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BP4, PM3_Supporting (ClinGen Hearing Loss VCEP specifications version 2; 11/22/2022) -

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

Mar 30, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2A Uncertain:1

Nov 06, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

USH2A-related disorder Uncertain:1

Sep 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The USH2A c.13396C>T variant is predicted to result in the amino acid substitution p.Pro4466Ser. This variant was reported, along with a large deletion in the same gene, in an individual with retinitis pigmentosa (Table S2, Carss et al. 2017. PubMed ID: 28041643). This variant was also described in the homozygous state in an individual with retinal disease (Turro et al. 2020. PubMed ID: 32581362). This variant is reported in 0.044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.049
Sift	Benign	0.61	T
Sift4G	Benign	0.93	T
Polyphen		0.045	B
Vest4		0.072
MVP		0.82
MPC		0.037
ClinPred		0.028	T
GERP RS		1.2
Varity_R		0.060
gMVP		0.34

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: rs138398671; hg19: chr1-215847857;