Submissions for variant NM_001081.3(CUBN):c.6359G>A (p.Trp2120Ter) (rs566060177)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000290525	SCV000361680	uncertain significance	Imerslund-Gräsbeck syndrome	2017-04-28	criteria provided, single submitter	clinical testing	The CUBN c.6359G>A (p.Trp2120Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00007 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of stop-gained variants and lack of clarifying evidence, the p.Trp2120Ter variant is classified as a variant of unknown significance, but suspicious for pathogenicity for megaloblastic anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV000290525	SCV001412274	pathogenic	Imerslund-Gräsbeck syndrome	2019-10-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2120*) in the CUBN gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs566060177, ExAC 0.007%). This variant has not been reported in the literature in individuals with CUBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 299439). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Loss-of-function variants in CUBN are known to be pathogenic (PMID: 15024727, 22929189). For these reasons, this variant has been classified as Pathogenic.

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