1-216321921-A-T

Variant names:

• chr1-216321921-A-T
• NM_206933.4:c.1606T>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_206933.4(USH2A):​c.1606T>A​(p.Cys536Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C536R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.96

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 18 ACMG points.

• PM1: In a disulfide_bond (size 16) in uniprot entity USH2A_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr1-216321921-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 48471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-216321921-A-T is Pathogenic according to our data. Variant chr1-216321921-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1297136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216321921-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1606T>A	p.Cys536Ser	missense_variant	Exon 9 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1606T>A	p.Cys536Ser	missense_variant	Exon 9 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1606T>A	p.Cys536Ser	missense_variant	Exon 9 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.1606T>A	p.Cys536Ser	missense_variant	Exon 9 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.1606T>A	p.Cys536Ser	missense_variant	Exon 9 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome Pathogenic:1

Mar 18, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.1606T>A (p.Cys536Ser) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes (gnomAD). c.1606T>A has been reported in the literature in individuals affected with Usher Syndrome. 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. Another missense change affecting this amino acid has been determined to be pathogenic (p.Cys536Arg), suggesting this may be a functionally important residue. The following publications have been ascertained in the context of this evaluation (PMID: 16963483, 31998945, 34203967). ClinVar contains an entry for this variant (Variation ID: 1297136). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys536 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10909849, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1297136). This missense change has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16963483, 31998945; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 536 of the USH2A protein (p.Cys536Ser). -

Retinitis pigmentosa Pathogenic:1

Jan 09, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Cys536Ser variant in USH2A was identified by our study in 1 individual with Retinitis Pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (PMID: 34906470). This variant was detected in the compound heterozygous state along with a pathogenic variant (Variation ID: 2356). The phase of these variants are unknown at this time. The p.Cys536Ser variant in USH2A has been reported in 1 individual with Usher syndrome and Retinitis Pigmentosa (PMID: 38219857), and has been identified in 0.000085% (1/1179878) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033273). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 1297136) and has been interpreted as pathogenic by Labcorp and likely pathogenic by Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 2 affected individuals, both were compound heterozygotes that carried a reported pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Cys536Ser variant is pathogenic (Variation ID: 2356, 2351; PMID: 34906470, 31998945). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position (p.Cys536Arg) has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (Variation ID: 48471). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PM3, PP3_moderate, PM2_supporting, PM5_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.94		Gain of disorder (P = 0.0046);Gain of disorder (P = 0.0046);
MVP		0.94
MPC		0.25
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-216495263;