Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000345657 | SCV000349487 | likely benign | Pyropoikilocytosis, hereditary | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
| Illumina Laboratory Services, |
RCV000404574 | SCV000349488 | likely benign | Hereditary spherocytosis type 3 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
| Illumina Laboratory Services, |
RCV000013717 | SCV000349489 | likely benign | Elliptocytosis 2 | 2017-04-27 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. |
| ARUP Laboratories, |
RCV001508911 | SCV000884578 | benign | not provided | 2023-10-27 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV001508911 | SCV001715347 | likely pathogenic | not provided | 2023-11-14 | criteria provided, single submitter | clinical testing | Spectrin Jendouba is a missense alteration in alpha spectrin that has long been associated with elliptocytosis. In our opinion, Spectrin Jendouba erroneously is classified as benign due to automated filters and strict cut-offs to classify alterations with MAF >5% as benign because this alteration has a high MAF in some subpopulations in population databases. For hereditary elliptocytosis a higher than 5% MAF may be acceptable, particularly in persons with ancestry from the malaria belt. Because it usually causes little other clinical manifestations, HE is under diagnosed, but is estimated to be 1 in 2000 – 1 in 4000 worldwide and up to 1 in 50 in African/African American sub-populations (UpToDate). Therefore, we suggest an exception from BA1 for SPTA1 gene based on the likely enrichment of disorder-causing alleles in ancestral populations where malaria is endemic. There is heterozygous advantage, particularly in genes affecting RBCs (Lelliott 2015 PMID 26215182), similar to what is suggested by the Hemoglobinopathy Variant Curation Expert Panel (Kountouris 2022 PMID 34510646). In regards to the specific pathogenicity of Spectrin Jendouba, there are numerous reports in the literature of its association with elliptocytosis and other RBC membranopathies if co-inherited with pathogenic alterations (Niss 2016 PMID 27667160, Alloisio 1992 PMID: 1638030, Kim 2021 PMID 33556202, Van Vuren 2019 PMID: 31723846). Most hereditary elliptocytosis variants are found in the C-terminal of helices 3. (Alloisio 1992 PMID: 1638030). This alteration occurs in helix 3, distant from the spectrin head-to-head self-association site resulting in a mild defect in spectrin dimer self-association. Our internal data including peripheral blood smear review showed all instances of Spectrin Jendouba presented with some red blood cell abnormality (mainly elliptocytes, however, when found with alphaLELY, also poikilocytes, spherocytes). Overall, based on the available evidence, we classify this variant as likely pathogenic. |
| Invitae | RCV001508911 | SCV003245183 | benign | not provided | 2024-01-29 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000013717 | SCV000033964 | pathogenic | Elliptocytosis 2 | 1992-08-01 | no assertion criteria provided | literature only |