ClinVar Miner

Submissions for variant NM_007123.5(USH2A):c.2299del (p.Glu767fs) (rs80338903)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824793 SCV000065508 pathogenic Usher syndrome; Rare genetic deafness 2014-09-30 criteria provided, single submitter clinical testing The p.Glu767fs variant in USH2A is a common pathogenic variant known to be assoc iated with Usher syndrome (Weston 2000, Dreyer 2000, Dreyer 2001, Najera 2002, O uyang 2004, Aller 2004).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254870 SCV000225952 pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000191141 SCV000245550 pathogenic Retinitis pigmentosa 39 2015-06-28 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory with 2 missense variants [G2224C, E3448K; phase undetermined] in a 32-year-old female with retinitis pigmentosa. Variant pathogenic in recessive state; heterozygotes are carriers.
GeneDx RCV000254870 SCV000321994 pathogenic not provided 2018-12-10 criteria provided, single submitter clinical testing The c.2299delG variant accounts for 16%-44% of USH2A variants and has been identified in patients with Usher syndrome type II, atypical Usher syndrome, and non-syndromic autosomal recessive retinitis pigmentosa (arRP) (Dreyer et al., 2001; Aller et al., 2004; Seyedahmadi et al., 2004; Aller et al., 2010). The c.2299delG variant causes a frameshift starting with codon Glutamic Acid 767, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 21 of the new reading frame, denoted p.Glu767SerfsX21. This common variant is predicted to disrupt an exonic splicing enhancer and instead create an exonic splicing silencer in exon 13, thereby diminishing the splicing of exons 12 and 13 (Lenassi et al., 2014). The c.2299delG variant is observed in 55/34402 (0.16%) alleles from individuals of Latino background and in 12/8252 (0.15%) alleles from individuals of European American background in large population cohorts (Lek et al., 2016; Exome Variant Server). Based on currently available evidence, we interpret c.2299delG as a pathogenic variant.
Ambry Genetics RCV000623326 SCV000740743 likely pathogenic Inborn genetic diseases 2014-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735362 SCV000854516 pathogenic Short stature; Cognitive impairment; High palate; Distal arthrogryposis; Anxiety; Brisk reflexes; Dysautonomia; Abnormality of the upper limb; Multiple joint contractures; Dislocated radial head; Abnormality of upper limb joint; Chronic pain; Abnormality of upper limb bone criteria provided, single submitter clinical testing
Invitae RCV000254870 SCV000940875 pathogenic not provided 2020-01-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu767Serfs*21) in the USH2A gene. It is expected to result in an absent or disrupted protein product. This variant is clearly defined as an Usher syndrome type II causative allele, accounting for 16-44% of disease alleles, and has also been reported in individuals affected with non-syndromic autosomal recessive retinitis pigmentosa (PMID: 9624053, 14970843, 15325563, 11402400, 25404053, 25097241). This variant is also known as 2314delG in the literature. ClinVar contains an entry for this variant (Variation ID: 2351). Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10909849, 20507924, 24944099, 25649381). For these reasons, this variant has been classified as Pathogenic.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000002445 SCV001156376 pathogenic Usher syndrome, type 2A 2019-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000453 SCV001157289 pathogenic not specified 2018-07-31 criteria provided, single submitter clinical testing The Glu767fs variant (rs80338903) has been observed in multiple cohorts of patients with Usher Syndrome, Type II (selected references: Eudy 1998, Dreyer 2001, Aller 2010). It is one of the most common pathogenic alleles of USH2A, and it is estimated that this variant accounts for 16% (Weston 2000) to 76% (Ouyang 2004) of all pathogenic USH2A variant. This variant is listed in the Genome Aggregation Database (gnomAD) database with a frequency in Latino populations of 0.20% (identified in 34 out of 34,442 chromosomes).
Baylor Genetics RCV000002445 SCV001162881 pathogenic Usher syndrome, type 2A criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000002445 SCV001194141 pathogenic Usher syndrome, type 2A 2019-12-17 criteria provided, single submitter clinical testing NM_206933.2(USH2A):c.2299delG(aka E767Sfs*21) is classified as pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 10909849 and 24607488. Classification of NM_206933.2(USH2A):c.2299delG(aka E767Sfs*21)is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Blueprint Genetics RCV000210326 SCV001239242 pathogenic Retinal dystrophy 2019-08-15 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000002445 SCV001244816 pathogenic Usher syndrome, type 2A 2018-05-29 criteria provided, single submitter clinical testing A heterozygous deletion variant was identified, NM_206933.2(USH2A):c.2299delG in exon 13 of USH2A.This deletion creates a frameshift from amino acid position 767, introducing a stop codon 21 residues downstream, NP_996816.2(USH2A):p.(Glu767Serfs*21). This variant is predicted to result in loss of protein function either through truncation (~80% of the protein, including multiple functional domains) or nonsense-mediated decay.This variant is present in the gnomAD population database at a frequency of 0.06% (189/276498 heterozygotes, 0 homozygotes). It has been previously reported as a common pathogenic variant in multiple patients/families with Usher syndrome type II and nonsyndromic autosomal recessive retinitis pigmentosa (Clinvar).It has also been reported to segregate with disease in at least one family (Niepokoj K. et al. 2018). In addition, other truncating/frameshift variants downstream of c.2299delG in USH2A have been reported as pathogenic in individuals with Usher syndrome (ClinVar). Based on current information, this variant has been classified as PATHOGENIC.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254870 SCV001248858 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill RCV001095692 SCV001251499 pathogenic USH2A-Related Disorders criteria provided, single submitter research The c.2299delG (p.E767Sfs) variant is one of the most common pathogenic variants in USH2A and has been previously reported in multiple individuals with Usher syndrome type IIA or nonsyndromic retinitis pigmentosa (PMID: 18641288; 11402400; 15326663).
Integrated Genetics/Laboratory Corporation of America RCV000504641 SCV001362171 pathogenic Usher syndrome 2019-10-25 criteria provided, single submitter clinical testing Variant summary: USH2A c.2299delG (p.Glu767SerfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00076 in 250832 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher syndrome (0.00076 vs 0.013), allowing no conclusion about variant significance. c.2299delG has been reported in the literature in multiple individuals affected with Usher syndrome. This variant appears to be a common USH2A mutation contributing to Usher Syndrome Type II (e.g. Aller_2004, Calzetti_2018 and Gene Reviews). Lenassi et al suggest that this change could disrupt an exonic splicing enhancer and create an exonic splicing silencer within exon 13 and therefore affect splicing of exons 12 and 13 of USH2A (Lenassi_2014). Nine ClinVar submitters (evaluation after 2014) cite this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000002445 SCV000022603 pathogenic Usher syndrome, type 2A 2009-12-01 no assertion criteria provided literature only
GeneReviews RCV000032524 SCV000056187 pathologic Retinitis pigmentosa 2010-12-23 no assertion criteria provided curation Converted during submission to Pathogenic.
Centre for Genomic Medicine, Manchester,Central Manchester University Hospitals RCV000210326 SCV000259101 pathogenic Retinal dystrophy 2015-01-30 no assertion criteria provided clinical testing
Counsyl RCV000191141 SCV000490146 pathogenic Retinitis pigmentosa 39 2016-08-18 no assertion criteria provided clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000032524 SCV000598799 pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504641 SCV000598800 pathogenic Usher syndrome 2015-01-01 no assertion criteria provided research
Human Genetics - Radboudumc,Radboudumc RCV000191141 SCV000804740 pathogenic Retinitis pigmentosa 39 2016-09-01 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000504641 SCV000926729 pathogenic Usher syndrome 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000032524 SCV000926730 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787895 SCV000926911 pathogenic Macular dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787897 SCV000926915 pathogenic Cone-rod dystrophy 2018-04-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787899 SCV000926917 pathogenic Congenital stationary night blindness 2018-04-01 no assertion criteria provided research

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