Submissions for variant NM_003126.4(SPTA1):c.1703G>A (p.Arg568His)

dbSNP: rs200829664

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756694	SCV000884584	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The SPTA1 c.1703G>A; p.Arg568His variant (rs200829664, ClinVar Variation ID: 618384) has been reported in an individual with spherocytosis, however, this individual also carried a variant in another gene that may explain the phenotype (Tole 2020). This variant is found in the general population with an overall allele frequency of 0.11% (308/280764 alleles) in the Genome Aggregation Database (v2.1.1). Additionally, another variant at this codon (c.1703G>C, p.Arg568Pro) has been reported in an individual with a suspicion of spherocytosis (Russo 2018). Computational analyses predict that the p.Arg568His variant is neutral (REVEL: 0.117). While the high population frequency suggests that this is likely a benign variant, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Russo R et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. Am J Hematol. 2018 May. PMID: 29396846. Tole S et al. Genotype-phenotype correlation in children with hereditary spherocytosis. Br J Haematol. 2020 Nov. PMID: 32436265.
Illumina Laboratory Services, Illumina	RCV001098198	SCV001254548	uncertain significance	Hereditary spherocytosis type 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001098199	SCV001254549	likely benign	Elliptocytosis 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001098200	SCV001254550	uncertain significance	Pyropoikilocytosis, hereditary	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000756694	SCV002102693	uncertain significance	not provided	2022-02-17	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in an individual with hereditary spherocytosis, but a second variant in SPTA1 was not reported, and a potentially causative variant was identified in another gene (Tole et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32436265)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756694	SCV002413120	likely benign	not provided	2025-01-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000756694	SCV005412483	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	BP4