Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Clinical Services Laboratory, |
RCV000778276 | SCV000914451 | uncertain significance | Imerslund-Gräsbeck syndrome | 2017-04-28 | criteria provided, single submitter | clinical testing | The CUBN c.5913_5916delTACC (p.Thr1972LeufsTer10) variant results in a frameshift and is predicted to result in 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 p.Thr1972LeufsTer10 variant is reported at a frequency of 0.00094 in the African American population of the Exome Sequencing Project, including in a homozygous state in two individuals. However, individuals with megaloblastic anemia may not come to medical attention. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, the p.Thr1972LeufsTer10 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. |
| Laboratory for Molecular Medicine, |
RCV000778276 | SCV000967607 | likely pathogenic | Imerslund-Gräsbeck syndrome | 2019-01-04 | criteria provided, single submitter | clinical testing | The p.Thr1972LeufsX10 variant in CUBN has not been previously reported in indivi duals with Imerslund-Grasbeck syndrome or megaloblastic anemia but has been iden tified in 12/128804 of European chromosomes by gnomAD (http://gnomad.broadinstit ute.org). Although this variant has been seen in the general population, its fre quency is low enough to be consistent with a recessive carrier frequency. This v ariant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1972 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a trunca ted or absent protein. Loss of function of the CUBN gene is an established disea se mechanism in autosomal recessive Imerslund-Grasbeck syndrome. In summary, alt hough additional studies are required to fully establish its clinical significan ce, this variant is likely pathogenic. ACMG/AMP criteria applied: PVS1, PM2 |