Submissions for variant NM_206933.4(USH2A):c.12448A>G (p.Thr4150Ala)

gnomAD frequency: 0.00001  dbSNP: rs1172628170

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000585084	SCV000692663	likely pathogenic	not provided	2017-10-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Institute for Ophthalmic Research	RCV001003256	SCV001162721	pathogenic	Retinitis pigmentosa	2020-01-09	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269243	SCV001448563	uncertain significance	not specified	2020-11-24	criteria provided, single submitter	clinical testing	Variant summary: USH2A c.12448A>G (p.Thr4150Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR0003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12448A>G has been reported in the literature in at-least three individuals, once as a solo allele in a family with Retinitis Pigmentosa (RP), second as a solo complex allele, c.[12448A>G;5012G>A] in a family with RP (Sharon_2020), and third as a compound heterozygous genotype (with c.1841-2A>G) in an individual with sporadic RP (Weisschuh_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic(n=2). At-least two of these submitters can be traced to an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000585084	SCV002121408	uncertain significance	not provided	2021-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with alanine at codon 4150 of the USH2A protein (p.Thr4150Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 31456290, 32531858). ClinVar contains an entry for this variant (Variation ID: 493061). 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: "Benign"; Align-GVGD: "Class C55"). 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.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001003256	SCV001161338	likely pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
Natera, Inc.	RCV001835857	SCV002088303	uncertain significance	Usher syndrome type 2A	2020-12-22	no assertion criteria provided	clinical testing