Submissions for variant NM_206933.4(USH2A):c.9433C>T (p.Leu3145Phe)

gnomAD frequency: 0.00001  dbSNP: rs267598373

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001252675	SCV001428434	uncertain significance	Usher syndrome	2020-07-28	reviewed by expert panel	curation	The c.9433C>T (p.Leu3145Phe) variant in USH2A is present in 0.0033% (1/30612) of South Asian allele in gnomAd v2.1.1 and in 0.0074% (1/13568) of Latino alleles in gnomAD v3 (PM2). This variant has been detected in 1 proband with bilateral sensorineural hearing loss in a homozygous state (PM3_Supporting, PMID: 26806561). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein (PP3 not met). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PM3_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036584	SCV001199957	pathogenic	not provided	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 3145 of the USH2A protein (p.Leu3145Phe). This variant is present in population databases (rs267598373, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Usher syndrome and/or retinitis pigmentosa (PMID: 26667666, 26806561, 26927203, 32531858; internal data). ClinVar contains an entry for this variant (Variation ID: 73556). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001073325	SCV001238864	pathogenic	Retinal dystrophy	2018-11-20	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723641	SCV001950413	uncertain significance	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Leu3145Phe variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PM3-P. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab.
CeGaT Center for Human Genetics Tuebingen	RCV001036584	SCV002562980	pathogenic	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498352	SCV002812802	likely pathogenic	Usher syndrome type 2A; Retinitis pigmentosa 39	2024-04-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460656	SCV004208290	likely pathogenic	Retinitis pigmentosa 39	2024-03-04	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073325	SCV005070875	likely pathogenic	Retinal dystrophy	2021-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001036584	SCV001922815	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001036584	SCV001959788	uncertain significance	not provided		no assertion criteria provided	clinical testing