Submissions for variant NM_206933.4(USH2A):c.4338_4339del (p.Cys1447fs)

dbSNP: rs111033367

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV000710335	SCV000840529	pathogenic	Usher syndrome	2018-09-25	reviewed by expert panel	curation	The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID: 20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000710335	SCV000065536	pathogenic	Usher syndrome	2019-03-19	criteria provided, single submitter	clinical testing	The p.Cys1447GlnfsX29 variant in USH2A has been reported in 14 individuals with Usher syndrome and 21 individuals with autosomal recessive retinitis pigmentosa, 17 of whom were homozygous or compound heterozygous (Ebermann 2009, Eudy 1998, Seyedahmedi 2004, Kimberling 2010, Sandberg 2008). This variant has also been identified in 0.0008% (1/113304) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1447 and leads to a premature stop codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, the p.Cys1447GlnfsX29 variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2.
Illumina Laboratory Services, Illumina	RCV000310917	SCV000354106	pathogenic	USH2A-Related Disorders	2017-04-28	criteria provided, single submitter	clinical testing	The USH2A c.4338_4339delCT (p.Cys1447GlnfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Cys1447GlnfsTer29 variant has been reported in six studies in which it is found in a total of 22 individuals with USH2A-related disorders, including in seven in a homozygous state, in two in a compound heterozygous state, and in 13 in a heterozygous state where a second variant was not found (Eudy et al. 1998; Weston et al. 2000; Seyedahmadi et al. 2004; Ebermann et al. 2009; Ebermann et al. 2010; Kimberling et al. 2010). The p.Cys1447GlnfsTer29 variant was absent from 493 controls but is reported at a frequency of 0.000008 in the European (non-Finnish) population of the Genome Aggregation Database. This is based on one allele only in a region of good sequence coverage so the variant is presumed rare. Based on the potential impact of frameshift variants and supporting evidence, the p.Cys1447GlnfsTer29 variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000793722	SCV000933089	pathogenic	not provided	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys1447Glnfs*29) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs111033367, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 9624053, 20440071). ClinVar contains an entry for this variant (Variation ID: 2353). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000793722	SCV001167822	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10729113, 15325563, 24944099, 18665195, 30311386, 9624053, 20440071, 25425308, 21234346, 20613545, 18641288, 31047384, 32853555, 34313030, 34039936)
Blueprint Genetics	RCV001073308	SCV001238846	pathogenic	Retinal dystrophy	2018-11-09	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000310917	SCV001251498	likely pathogenic	USH2A-Related Disorders		criteria provided, single submitter	research	The USH2A c.4338_4339delCT (p.C1447Qfs) frameshift variant has been previously reported in multiple individuals with Usher syndrome, type IIA or nonsyndromic retinitis pigmentosa (PMID: 18641288; 15325563).
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000984013	SCV001573445	pathogenic	Retinitis pigmentosa 39	2021-04-08	criteria provided, single submitter	research	The USH2A c.4338_4339del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1-S, PP4. Based on this evidence we have classified this variant as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002482816	SCV002779395	pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-04-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984013	SCV004208287	pathogenic	Retinitis pigmentosa 39	2023-09-03	criteria provided, single submitter	clinical testing
OMIM	RCV000002447	SCV000022605	pathogenic	Usher syndrome type 2A	2010-06-01	no assertion criteria provided	literature only
Counsyl	RCV000984013	SCV000789062	pathogenic	Retinitis pigmentosa 39	2017-01-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000002447	SCV001462270	pathogenic	Usher syndrome type 2A	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000310917	SCV002074993	not provided	USH2A-Related Disorders		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-24-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.