Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
ARUP Laboratories, |
RCV001509084 | SCV001477768 | pathogenic | not provided | 2023-11-03 | criteria provided, single submitter | clinical testing | The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in at least nine individuals affected with either elliptocytosis or hereditary pyropoikilocytosis (Costa 2005, Dalla Venezia 1993, Gallagher 1992, Glele-Kakai 1996). This variant is also reported in ClinVar (Variation ID: 12857). In vitro functional analyses demonstrate reduced protein folding and dimerization (Randles 2013). This variant is found in the African / African-American population with an allele frequency of 0.07% (52/75,030 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Based on available information, this variant is considered to be pathogenic. REFERENCES Costa DB et al. A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. Blood. 2005 Dec 15. PMID: 16150946 Dalla Venezia N et al. An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. Hum Genet. 1993 Feb. PMID: 8444470 Gallagher PG et al. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar. PMID: 1541680 Glele-Kakai C et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol. 1996 Oct. PMID: 8857939 Randles LG et al. Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. FEBS J. 2013 Feb. PMID: 23241237 |
Mayo Clinic Laboratories, |
RCV001509084 | SCV001715607 | pathogenic | not provided | 2023-05-09 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001509084 | SCV001770621 | uncertain significance | not provided | 2023-10-18 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23241237, 8857939, 16150946, 1541680, 8444470, 18815189) |
Revvity Omics, |
RCV001509084 | SCV002023642 | likely pathogenic | not provided | 2023-08-31 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001509084 | SCV003523882 | uncertain significance | not provided | 2023-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). This variant is present in population databases (rs121918643, gnomAD 0.08%). This missense change has been observed in individual(s) with spherocytosis or pyropoikilocytosis (PMID: 1541680, 8068958, 8444470, 8857939, 18815189). ClinVar contains an entry for this variant (Variation ID: 12857). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPTA1 protein function with a positive predictive value of 80%. 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. |
OMIM | RCV000013714 | SCV000033961 | pathogenic | Pyropoikilocytosis, hereditary | 2005-12-15 | no assertion criteria provided | literature only | |
OMIM | RCV000013715 | SCV000033962 | pathogenic | Elliptocytosis 2 | 2005-12-15 | no assertion criteria provided | literature only |