Submissions for variant NM_001081.4(CUBN):c.3988C>T (p.His1330Tyr)

gnomAD frequency: 0.00044  dbSNP: rs149749419

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001922389	SCV002177205	uncertain significance	Imerslund-Grasbeck syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with tyrosine at codon 1330 of the CUBN protein (p.His1330Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs149749419, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with CUBN-related conditions. 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 tyrosine 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.
Fulgent Genetics, Fulgent Genetics	RCV002503527	SCV002815986	uncertain significance	Imerslund-Grasbeck syndrome type 1; Proteinuria, chronic benign	2022-02-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004743631	SCV005345104	likely benign	CUBN-related disorder	2024-09-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).