Submissions for variant NM_206933.4(USH2A):c.13133C>T (p.Pro4378Leu)

gnomAD frequency: 0.00026  dbSNP: rs570277510

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001043922	SCV001207691	likely pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4378 of the USH2A protein (p.Pro4378Leu). This variant is present in population databases (rs570277510, gnomAD 0.07%). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (Invitae). ClinVar contains an entry for this variant (Variation ID: 841656). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Blueprint Genetics	RCV001073415	SCV001238956	likely pathogenic	Retinal dystrophy	2019-01-23	criteria provided, single submitter	clinical testing
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV001805991	SCV001745855	uncertain significance	Usher syndrome type 2A; Retinitis pigmentosa 39	2019-10-08	criteria provided, single submitter	clinical testing	Two variants in this gene (USH2A) were found to be in cis (both were inherited form the mother) in a young male with postlingual bilateral severe hearing loss
GeneDx	RCV001043922	SCV002003509	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	Identified in a patient with hearing loss who was also heterozygous for an USH2A variant on the same allele (in cis) and two PCDH15 variants that were also on the same allele (in cis) with each other in published literature (Van Heurck et al., 2021); 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: 34440452)
Ambry Genetics	RCV003160314	SCV003868343	uncertain significance	Inborn genetic diseases	2023-01-23	criteria provided, single submitter	clinical testing	The c.13133C>T (p.P4378L) alteration is located in exon 63 (coding exon 62) of the USH2A gene. This alteration results from a C to T substitution at nucleotide position 13133, causing the proline (P) at amino acid position 4378 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001272944	SCV001455395	uncertain significance	Usher syndrome type 2A	2019-11-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004733115	SCV005350639	uncertain significance	USH2A-related disorder	2024-09-13	no assertion criteria provided	clinical testing	The USH2A c.13133C>T variant is predicted to result in the amino acid substitution p.Pro4378Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD, which may be to common to be a primary cause of disease. Although we suspect that this variant may benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.