ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.5167G>C (p.Gly1723Arg)

gnomAD frequency: 0.00003  dbSNP: rs1342455785
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667892 SCV000792404 likely pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2017-06-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001067077 SCV001232110 pathogenic not provided 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1723 of the USH2A protein (p.Gly1723Arg). This variant also falls at the last nucleotide of exon 25, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with USH2A-related conditions (PMID: 24944099, 25404053, 26667666). ClinVar contains an entry for this variant (Variation ID: 552599). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075428 SCV001241051 pathogenic Retinal dystrophy 2018-08-26 criteria provided, single submitter clinical testing
GeneDx RCV001067077 SCV002756935 likely pathogenic not provided 2022-11-15 criteria provided, single submitter clinical testing Located at the last nucleotide position of the exon 25, which is part of the splice donor site, and predicted to result in aberrant splicing; although in the absence of functional evidence, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 25404053, 24944099, 26667666, 36362125)
Fulgent Genetics, Fulgent Genetics RCV000667892 SCV002810442 likely pathogenic Usher syndrome type 2A; Retinitis pigmentosa 39 2021-07-16 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004533468 SCV004117507 pathogenic USH2A-related disorder 2023-12-12 criteria provided, single submitter clinical testing The USH2A c.5167G>C variant is predicted to result in the amino acid substitution p.Gly1723Arg. This variant has been reported in the heterozygous state along with other USH2A loss-of-function variants in multiple individuals with Usher syndrome or retinitis pigmentosa (Table S1, Baux et al. 2014. PubMed ID: 24944099, Table 3, Aparisi et al. 2014. PubMed ID: 25404053; Table 1, Ge et al. 2015. PubMed ID: 26667666). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. An in vitro experimental study suggests this variant weakens the canonical splice donor site leading to the skipping of exon 25 and/or 26 (Table 2, Reurink et al. 2022. PubMed ID: 36362125). This variant is interpreted as pathogenic.
Genome-Nilou Lab RCV003451666 SCV004181837 likely pathogenic Retinitis pigmentosa 39 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001276250 SCV004181838 likely pathogenic Usher syndrome type 2A 2023-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV003451666 SCV004208257 pathogenic Retinitis pigmentosa 39 2024-03-16 criteria provided, single submitter clinical testing
Natera, Inc. RCV001276250 SCV001462258 pathogenic Usher syndrome type 2A 2020-09-16 no assertion criteria provided clinical testing

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