ClinVar Miner

Submissions for variant NM_007123.5(USH2A):c.1346G>A (p.Arg449His) (rs766715882)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778221 SCV000914387 uncertain significance Usher syndrome, type 2A 2017-04-28 criteria provided, single submitter clinical testing The USH2A c.1346G>A (p.Arg449His) missense variant has been reported in one study in which it is found in a compound heterozygous state with a frameshift variant in two siblings under the age of three with bilateral hearing loss (Mutai et al. 2013). The variant was also found in a heterozygous state in one unaffected parent. The p.Arg449His variant was reported in five of 378 Japanese control chromosomes in a heterozygous state and is reported at a frequency of 0.000175 in the East Asian population of the Genome Aggregation Database. Based on the evidence, the p.Arg449His variant is classified as a variant of unknown significance but suspicious for pathogenicity for Usher syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001049330 SCV001213375 uncertain significance not provided 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 449 of the USH2A protein (p.Arg449His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs766715882, ExAC 0.006%). This variant has been observed to segregate with autosomal recessive hearing loss in a family (PMID: 24164807). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001099202 SCV001255634 uncertain significance Retinitis pigmentosa 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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