ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.4338_4339del (p.Cys1447fs) (rs111033367)

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Total submissions: 11
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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 (, 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, Partners HealthCare 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 (, 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 Clinical Services Laboratory,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 2020-09-09 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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with Usher syndrome (PMID: 20440071, 9624053). ClinVar contains an entry for this variant (Variation ID: 2353). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000793722 SCV001167822 pathogenic not provided 2019-02-12 criteria provided, single submitter clinical testing The c.4338_4339delCT variant has been reported previously in association with Usher syndrome (Sandberg et al., 2008; Kimberling et al., 2010; Zein et al., 2015). The deletion causes a frameshift starting with codon Cystine 1447, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 29 of the new reading frame, denoted p.Cys1447GlnfsX29. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.4338_4339delCT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret this variant as pathogenic.
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.
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

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