Submissions for variant NM_206933.4(USH2A):c.11815G>A (p.Glu3939Lys)

gnomAD frequency: 0.00043  dbSNP: rs146264950

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155322	SCV000205008	uncertain significance	not specified	2018-04-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu3939Lys va riant in USH2A has been previously reported in 4 individuals with hearing loss a nd in 3 individuals with retinitis pigmentosa (Neveling 2012, Tajiguli 2016, Hae r-Wigman 2017, LMM data); however, none of these individuals had a second pathog enic variant identified in the USH2A gene. This variant has also been identified in 0.15% (15/10150) of Ashkenazi Jewish and 0.08% (97/125366) of European chrom osomes, including one homozygote, by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs146264950). Computational prediction too ls and conservation analysis do not provide strong support for or against an imp act to the protein. In summary, while the clinical significance of the p.Glu393 9Lys variant is uncertain, its frequency suggests that it is more likely to be b enign. ACMG/AMP Criteria applied: BS1_Supporting.
Counsyl	RCV000664687	SCV000788688	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2016-12-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244553	SCV001417782	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV001274938	SCV001736774	uncertain significance	Usher syndrome type 2A	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001274938	SCV001806747	uncertain significance	Usher syndrome type 2A	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579277	SCV001806748	uncertain significance	Retinitis pigmentosa 39	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155322	SCV002104154	uncertain significance	not specified	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.11815G>A (p.Glu3939Lys) results in a conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 250102 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00049 vs 0.011), allowing no conclusion about variant significance. c.11815G>A has been reported in the literature in individuals/families affected with retinitis pigmentosa and multifocal choroiditis (Neveling_2012, Tajiguli_2016, Haer-Wigman_2017, Jespersgaard_2019, McGowan_2020, Li_2021, Hufnagel_2022) but it has also been reported in unaffected homozygous individuals (gnomAD and PMID 34426522). In at least one of these reports, the variant was determined to not segregate in the affected family (Neveling_2012). These reports do not provide unequivocal conclusions about association of the variant with Usher Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Six classified as VUS, one submitter classified as Likely Benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000664687	SCV002781280	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2022-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001579277	SCV004206453	uncertain significance	Retinitis pigmentosa 39	2021-11-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001244553	SCV005093420	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	USH2A: BP4, BS1:Supporting
Breakthrough Genomics, Breakthrough Genomics	RCV001244553	SCV005187233	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001244553	SCV005198969	uncertain significance	not provided	2022-07-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001274938	SCV001459521	uncertain significance	Usher syndrome type 2A	2019-12-27	no assertion criteria provided	clinical testing