1-216200030-A-T

Variant names:

• chr1-216200030-A-T
• rs1064793287
• NM_206933.4:c.3408T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM5 PP3_Moderate PP5

The NM_206933.4(USH2A):​c.3408T>A​(p.Ser1136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,618 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. S1136N) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 1.31
• Publications: 0 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-AS1 (HGNC:40606): (USH2A antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-216200031-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 133312.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 1-216200030-A-T is Pathogenic according to our data. Variant chr1-216200030-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418534.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.3408T>A	p.Ser1136Arg	missense_variant	Exon 17 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.3408T>A	p.Ser1136Arg	missense_variant	Exon 17 of 72	1	NM_206933.4	ENSP00000305941.3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151796 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251178 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000342 AC: 5 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727216

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

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

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: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151796 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74124

African (AFR) AF: 0.00 AC: 0 AN: 41304

American (AMR) AF: 0.0000657 AC: 1 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Mar 12, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The USH2A c.3408T>A; p.Ser1136Arg variant, to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. However, another variant affecting the same codon, Ser1136Asn, was found in a patient with Usher syndrome (Le Quesne Stabej 2012). This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.0004% (identified on 1 out of 245,946 chromosomes) and is classified as likely pathogenic in ClinVar (ID: 418534). The serine at position 1136 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Ser1136Arg variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: probably damaging). Although the available information suggests that it may be pathogenic, the clinical significance of the p.Ser1136Arg variant cannot be determined with certainty. -

Dec 21, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A different missense change at this residue (S1136N) has been classified as likely pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (SCV000840537.3; Oza et al., 2018); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30311386) -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1136 of the USH2A protein (p.Ser1136Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of USH2A-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 418534). 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 expected to disrupt USH2A protein function with a positive predictive value of 95%. This variant disrupts the p.Ser1136 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22135276, 25991456, 27460420, 27957503, 28512305, 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. -

Usher syndrome Pathogenic:1

Jul 03, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.3408T>A (p.Ser1136Arg) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes. c.3408T>A has been observed in individuals affected with clinical features of Usher Syndrome and related disorders, including retinitis pigmentosa and/or hearing loss (internal data). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same codon has been classified as pathogenic (c.3407G>A, p.Ser1136Asn), supporting the critical relevance of codon 1136 to USH2A protein function. ClinVar contains an entry for this variant (Variation ID: 418534). Based on the evidence outlined above, the variant was classified as pathogenic. -

Rare genetic deafness Pathogenic:1

Nov 01, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser1136Arg variant in USH2A has been reported in 1 infant with congenital mild to moderate hearing loss who was compound heterozygous for a second USH2A v ariant, and the two variants segregated in an affected sibling. This variant has also been reported in ClinVar (Variation ID: 418534). Another amino acid change at the same position has been reported in 1 individual with Usher syndrome who was compound heterozygous for a second pathogenic USH2A variant (Le Quesne Stabe j 2012, Bonnet 2016). The p.Ser1136Arg variant has been identified in 1/33578 La tino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org/; dbSNP rs1064793287). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessiv e carrier frequency. Computational prediction tools and conservation analyses su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PP3, PM3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.6	H;H
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.70		Gain of MoRF binding (P = 0.0473);Gain of MoRF binding (P = 0.0473);
MVP		0.93
MPC		0.25
ClinPred		0.99	D
GERP RS		2.5
Varity_R		0.67
gMVP		0.83
Mutation Taster		=16/84	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: rs1064793287; hg19: chr1-216373372;