rs80338902

Variant names:

• chr1-216247118-C-A
• rs80338902
• NM_206933.4:c.2276G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PS4 PM3_Strong PP1_Strong BS1 PP4 PP3

This summary comes from the ClinGen Evidence Repository: The p.Cys759Phe variant in USH2A has been reported in 10 individuals with a clinical diagnosis of Usher Syndrome type II who were all confirmed compound heterozygous with a second pathogenic variant on the remaining allele (PMIDs: 16098008, 24944099, 29912909) (PM3_Strong). Note that scoring for PM3 was downgraded from PM3_VeryStrong to PM3_Strong since this variant has an allele frequency that meets criteria for BS1 (see below). Co-segregation with Usher II was demonstrated collectively in 2 affected and 13 unaffected siblings (LOD score: 2.23). When including all families affected with Usher II or an atypical Usher presentation (retinitis pigmentosa (RP) with some form of hearing loss), co-segregation can be identified in three affected and 26 unaffected siblings total (LOD score: 4.45) (PMID:29912909) (PP1_Strong). When considering those patients who present with isolated RP, the variant segregated in an additional 15 affected and 32 unaffected siblings (LOD score: 12.43) (PMIDs:10775529, 12525556, 21151602, 29912909). The filtering allele frequency (the lower threshold of the 95% CI of 72/35410) of the p.Cys759Phe variant in the Latino population in gnomAD is 0.17% and it has also been observed at the filtering allele frequency (the lower threshold of the 95% CI of 17/2536) of 0.43% across several Spanish or Latino populations published in the literature (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529; BS1). Although this allele frequency meets the threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants, other studies suggest it may still be associated with Usher syndrome, albeit with potentially reduced penetrance. The variant is statistically enriched in cohorts of Usher (2.00% (54/2704) in Usher patients compared to 0.67% (17/2536) as the highest and most ethnically matched published Spanish and Latino control populations; Fisher’s exact p value <0.0001) and RP patients (1.87% (109/5828) in RP patients compared to 0.71% in published Spanish and Latino controls; Chi-Square p value <0.0001) (PMIDs: 12525556, 12112664, 25262649, 26764160, 25261458, 25823529, 10909849, 12112664, 14970843, 15325563, 16098008, 17405132, 18273898, 19683999, 22004887, 21738395, 24944099, 25375654, 28041643, 29588463, 21151602, 25097241, 23591405, 25910913, 25649381, 29283788, 22135276, 22334370) (PS4). The association with Usher syndrome is particularly clear when paired with a predicted loss-of-function or other pathogenic variant compared to homozygous individuals who are more at risk to develop non-syndromic RP (PMIDs: 29912909 and 25375654). There may also be evidence of reduced penetrance for both hearing loss and RP as two homozygous individuals were documented to have no evidence of any phenotype through their 6th decade (PMIDs: 16098008, 12525556). The PP4 rule has also been applied to this variant given the combination of hearing loss and RP that is seen in these patients and that most patients were screened for other Usher genes. Lastly, computational prediction tools and conservation analysis suggest that the p.Cys759Phe variant may impact the protein (REVEL: 0.902), and an analysis using the homologous mouse laminin gamma 1 chain concluded that this variant is likely to disrupt disulfide bonding with the cysteine at position 747 (PMID:10909849) (PP3). In summary, the ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for Usher Syndrome outweighs its higher than expected allele frequency in population databases and other general population cohorts. Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome (ACMG codes applied: BS1, PS4, PM3_Strong, PP1_Strong, PP4, and PP3). Please note that patients with this variant may present with either Usher syndrome or with isolated RP. Isolated RP presentations are more common when the variant is seen in homozygosity as opposed to combined with a distinct pathogenic USH2A variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA252233/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:49 O:3
• Conservation: PhyloP100: 5.53
• Publications: 174 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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa 39

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206933.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	NM_206933.4	MANE Select	c.2276G>T	p.Cys759Phe	missense	Exon 13 of 72	NP_996816.3
	USH2A	NM_007123.6		c.2276G>T	p.Cys759Phe	missense	Exon 13 of 21	NP_009054.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USH2A	ENST00000307340.8	TSL:1 MANE Select	c.2276G>T	p.Cys759Phe	missense	Exon 13 of 72	ENSP00000305941.3
	USH2A	ENST00000366942.3	TSL:1	c.2276G>T	p.Cys759Phe	missense	Exon 13 of 21	ENSP00000355909.3
	USH2A	ENST00000674083.1		c.2276G>T	p.Cys759Phe	missense	Exon 13 of 73	ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000969 AC: 243 AN: 250722 AF XY: 0.000893

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00140

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00148 AC: 2158 AN: 1461782 Hom.: 5 Cov.: 31 AF XY: 0.00142 AC XY: 1029 AN XY: 727202

African (AFR) AF: 0.000269 AC: 9 AN: 33476

American (AMR) AF: 0.00177 AC: 79 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53414

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00178 AC: 1974 AN: 1111934

Other (OTH) AF: 0.00151 AC: 91 AN: 60394

GnomAD4 genome AF: 0.00131 AC: 199 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74418

African (AFR) AF: 0.000529 AC: 22 AN: 41562

American (AMR) AF: 0.00314 AC: 48 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00181 AC: 123 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000976 Hom.: 2

Bravo AF: 0.00149

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000782 AC: 95

EpiCase AF: 0.00169

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	not provided (11)
9	-	-	Usher syndrome type 2A (9)
8	-	-	Retinitis pigmentosa 39 (8)
4	-	-	Retinal dystrophy (4)
4	-	-	Retinitis pigmentosa (5)
4	-	-	Usher syndrome (4)
3	-	-	USH2A-related disorder (4)
2	-	-	Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 (3)
1	-	-	Autosomal recessive retinitis pigmentosa (1)
1	-	-	Ear malformation (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.98
MPC		0.27
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80338902; hg19: chr1-216420460; COSMIC: COSV99048434;