ClinVar Miner

Submissions for variant NM_003126.4(SPTA1):c.620T>C (p.Leu207Pro)

gnomAD frequency: 0.00019  dbSNP: rs121918643
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, 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, Mayo Clinic RCV001509084 SCV001715607 pathogenic not provided 2023-05-09 criteria provided, single submitter clinical testing
GeneDx 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, Revvity 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

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