Submissions for variant NM_206933.4(USH2A):c.3700A>G (p.Ile1234Val)

gnomAD frequency: 0.00005  dbSNP: rs200276882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041832	SCV000065528	likely benign	not specified	2010-11-15	criteria provided, single submitter	clinical testing	Ile1234Val in exon 17 of USH2A: This variant is not expected to have clinical si gnificance because this residue is not highly conserved across species and compu tational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest an impact to the pr otein. Of note, platypus, chicken and lizard also have a valine at this position .
Illumina Laboratory Services, Illumina	RCV000291877	SCV000354123	uncertain significance	Retinitis pigmentosa	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000346771	SCV000354124	uncertain significance	Usher syndrome type 2A	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000669144	SCV000793861	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2017-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV002513602	SCV003481296	uncertain significance	not provided	2022-05-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1234 of the USH2A protein (p.Ile1234Val). This variant is present in population databases (rs200276882, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48506). 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 valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV003162354	SCV003907621	uncertain significance	Inborn genetic diseases	2023-02-23	criteria provided, single submitter	clinical testing	The c.3700A>G (p.I1234V) alteration is located in exon 17 (coding exon 16) of the USH2A gene. This alteration results from a A to G substitution at nucleotide position 3700, causing the isoleucine (I) at amino acid position 1234 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.