Submissions for variant NM_003126.4(SPTA1):c.3230G>A (p.Arg1077His)

gnomAD frequency: 0.00249  dbSNP: rs199612744

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756706	SCV000884596	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV000756706	SCV001048046	likely benign	not provided	2022-08-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101375	SCV001257977	uncertain significance	Hereditary spherocytosis type 3	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101376	SCV001257978	uncertain significance	Elliptocytosis 2	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001101377	SCV001257979	uncertain significance	Pyropoikilocytosis, hereditary	2017-04-28	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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000756706	SCV001713074	uncertain significance	not provided	2022-07-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000756706	SCV003805539	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	Reported in a patient with hereditary hemolytic anemia who also harbored an additional missense variant in the SPTA1 gene (Vives-Corrons et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28195122, 32579932, 30485824, 28153049, 29544535, 28420421, 33074480)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000756706	SCV001550745	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SPTA1 p.Arg1077His variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs199612744), ClinVar (classified as a VUS by ARUP Laboratories) and Cosmic. The variant was also identified in control databases in 214 of 280646 chromosomes (1 homozygous) at a frequency of 0.000763 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 196 of 24178 chromosomes (freq: 0.008107), Latino in 12 of 35342 chromosomes (freq: 0.00034), South Asian in 2 of 30602 chromosomes (freq: 0.000065) and European (non-Finnish) in 4 of 128486 chromosomes (freq: 0.000031), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) or Other populations. The p.Arg1077 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.