Submissions for variant NM_003126.4(SPTA1):c.779T>C (p.Leu260Pro)

gnomAD frequency: 0.00006  dbSNP: rs121918634

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413397	SCV000491320	likely pathogenic	not provided	2024-09-19	criteria provided, single submitter	clinical testing	Observed in multiple individuals in published literature with hereditary elliptocytosis, either in the heterozygous or homozygous state and often found in combination with the alpha-Lely allele (PMID: 8857939, 2794061, 31539204, 37400730); Published functional studies demonstrate that L260P increased the stability of the closed dimer state, reduced tetramer assembly, and resulted in membrane destabilization (PMID: 23241237, 23974198); 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: 3597773, 23974198, 2794061, 31130284, 8857939, 31539204, 37400730, 35150601, 38103590, 18815189, 32641076, 23241237)
Mayo Clinic Laboratories, Mayo Clinic	RCV000413397	SCV001715605	pathogenic	not provided	2024-08-27	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000013697	SCV001984263	pathogenic	Elliptocytosis 2	2021-03-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413397	SCV002023639	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413397	SCV003523913	likely pathogenic	not provided	2024-04-06	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 260 of the SPTA1 protein (p.Leu260Pro). This variant is present in population databases (rs121918634, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal dominant hereditary elliptocytosis and autosomal recessive hereditary pyropoikilocytosis (PMID: 2794061, 8857939, 18815189, 31130284, 31539204, 32641076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12844). 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%. Experimental studies have shown that this missense change affects SPTA1 function (PMID: 23974198). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000013697	SCV004805424	likely pathogenic	Elliptocytosis 2	2024-03-25	criteria provided, single submitter	research
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798726	SCV005420374	pathogenic	Spherocytosis	2024-10-04	criteria provided, single submitter	research	PS3,PM3(strong),PP4,PM2,PP3
OMIM	RCV000013697	SCV000033944	pathogenic	Elliptocytosis 2	1989-10-01	no assertion criteria provided	literature only