Submissions for variant NM_206933.4(USH2A):c.4133T>C (p.Leu1378Pro)

dbSNP: rs2034852728

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001074304	SCV001239877	pathogenic	Retinal dystrophy	2019-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV001243846	SCV001417029	likely pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 866375). This missense change has been observed in individuals with Usher syndrome or retinitis pigmentosa (PMID: 22135276, 26927203). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1378 of the USH2A protein (p.Leu1378Pro).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471033	SCV002769102	uncertain significance	Usher syndrome type 2A	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline (exon 19). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (fibronectin type 3 domain; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been reported as probably pathogenic in a patient with Usher syndrome type 2 (PMID: 22135276, Deafness Variation Database). It is also reported as a VUS or unclassified, including in 2 patients with retinitis pigmentosa (LOVD; PMIDs: 28981474, 26927203). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323795	SCV004029981	pathogenic	Usher syndrome	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.4133T>C (p.Leu1378Pro) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250742 control chromosomes. c.4133T>C has been reported in the literature in multiple compound heterozygous individuals affected with clinical features of Usher Syndrome (e.g., Baux_2014, Pierrache_2016, Feenstra_2022, Comander_2017, Le Quesne Stabej_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24944099, 28981474, 36011334, 22135276, 26927203). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; one submitter classified the variant as a variant of uncertain significance, one classified it as likely pathogenic, and one cliassified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001243846	SCV004703535	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	USH2A: PM3:Strong, PM2