Submissions for variant NM_001355436.2(SPTB):c.6055T>C (p.Ser2019Pro)

dbSNP: rs121918648

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004906	SCV001164406	likely pathogenic	Hereditary spherocytosis type 2	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Ser2019Pro variant in SPTB was identified by our study in three unrelated individuals with spherocytosis. This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ser2019Pro variant in SPTB has been reported in 8 Laotian individuals with spherocytosis and segregated with disease in the homozygous or heterozygous state in 7 affected relatives from a two-generation family. The genotype of one affected individual was unknown. All individuals known to be homozygous for the variant were stillborn or died shortly after birth while all individuals known to be heterozygous for the variant had mild elliptocytosis (PMID: 7883966). This variant is located in the self-association region of the protein, a common site of pathogenic variation for hereditary elliptocytosis (PMID: 8844207). In summary, although additional studies are required to fully establish its clinical significance, the p.Ser2019Pro variant is likely pathogenic. ACMG/AMP Criteria applied: PM1, PM2, PP1_Moderate (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513020	SCV003442308	pathogenic	not provided	2024-05-12	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2019 of the SPTB protein (p.Ser2019Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary elliptocytosis and/or neonatal nonimmune hemolytic anemia (PMID: 7883966, 30198572). It has also been observed to segregate with disease in related individuals. This variant is also known as spectrin Providence. ClinVar contains an entry for this variant (Variation ID: 12837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SPTB function (PMID: 7883966, 8667615). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV002513020	SCV003827413	pathogenic	not provided	2022-03-14	criteria provided, single submitter	clinical testing
OMIM	RCV000013688	SCV000033935	pathogenic	Elliptocytosis 3	2018-04-25	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004724739	SCV005339608	pathogenic	SPTB-related disorder	2024-09-12	no assertion criteria provided	clinical testing	The SPTB c.6055T>C variant is predicted to result in the amino acid substitution p.Ser2019Pro. This variant is also referred to as spectrin Providence and has been noted to be common in individuals with severe inherited hemolytic anemia in the Thai population (Ittiwut et al. 2019. PubMed ID: 30198572; Songdej et al. 2024. PubMed ID: 35819869). It has been reported in the homozygous and compound heterozygous states in individuals with severe inherited hemolytic anemia (Gallagher et al. 1995. PubMed ID: 7883966; Ittiwut et al. 2019. PubMed ID: 30198572; Songdej et al. 2024. PubMed ID: 35819869). Individuals heterozygous for this variant have been reported to have a milder elliptocytosis phenotype (Gallagher et al. 1995. PubMed ID: 7883966; Songdej et al 2024. PubMed ID: 35819869). In vitro experimental studies indicate this variant impacts protein function (Gallagher et al. 1995. PubMed ID: 7883966; Weed et al. 1996. PubMed ID: 8667615). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.