Submissions for variant NM_206933.4(USH2A):c.1346G>A (p.Arg449His)

gnomAD frequency: 0.00005  dbSNP: rs766715882

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049330	SCV001213375	uncertain significance	not provided	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 449 of the USH2A protein (p.Arg449His). This variant is present in population databases (rs766715882, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive hearing loss (PMID: 24164807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 631593). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. 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 Laboratory Services, 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.
Genome-Nilou Lab	RCV003453611	SCV004182884	uncertain significance	Retinitis pigmentosa 39	2023-11-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000778221	SCV004182885	uncertain significance	Usher syndrome type 2A	2023-11-04	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003889976	SCV004708067	likely benign	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Natera, Inc.	RCV000778221	SCV002093990	uncertain significance	Usher syndrome type 2A	2020-01-26	no assertion criteria provided	clinical testing