Submissions for variant NM_003126.4(SPTA1):c.460_462dup (p.Leu155dup)

dbSNP: rs757679761

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598724	SCV000710385	likely pathogenic	not provided	2025-02-12	criteria provided, single submitter	clinical testing	Published functional studies on red blood cells extracted from patients with hereditary elliptocytosis (HE) who harbor the c.460_462dupTTG variant, show increased spectrum dimers as compared to wild type red blood cells, suggesting the variant causes a structural defect in the spectrin molecule affecting tetramer formation (PMID: 4027386); In-frame duplication of 1 amino acid in a non-repeat region; Also known as alpha I-65 or L148dup; This variant is associated with the following publications: (PMID: 2567189, 3597773, 2794061, 1353056, 27667160, 8857939, 30393954, 31040790, 34426522, 31589614, 32623341, 34889366, 34553410, 33074480, 34201899, 37016817, 4027386)
Baylor Genetics	RCV001336016	SCV001529291	pathogenic	Pyropoikilocytosis, hereditary	2018-10-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Heterozygous p.L154dup has been previously reported in patients with Sp alpha I/65 hereditary elliptocytosis [PMID 2567189, 8857939]
Mayo Clinic Laboratories, Mayo Clinic	RCV000598724	SCV001715609	pathogenic	not provided	2024-05-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000598724	SCV002023635	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000598724	SCV002049268	pathogenic	not provided	2024-06-11	criteria provided, single submitter	clinical testing	The SPTA1 c.460_462dup, p.Leu155dup variant (rs757679761), also known as alpha(I-65), is reported in the literature multiple related and unrelated individuals and families, primarily of African descent, affected with hereditary elliptocytosis, although with variable clinical severity (del Giudice et al., 1992; Garbarz et al., 1986; Marchesi et al., 1987; Niss et al., 2016; Qualtieri et al., 1995; Roux et al., 1989; Sahr et al., 1989). This variant has also been reported in trans (on opposite chromosomes) from the alpha-LELY allele in two individuals affected with hereditary pyropoikilocytosis (Niss et al., 2016). In vitro functional analyses demonstrate impaired SPTA1 oligomer formation (Marchesi et al., 1987). This variant is reported as likely pathogenic by one laboratory in ClinVar (Variation ID: 12847). This variant is found predominantly in the African population with an overall allele frequency of 0.095% (23/24192 alleles, including no homozygotes) in the Genome Aggregation Database. This variant inserts a single leucine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000598724	SCV002214445	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This variant, c.460_462dup, results in the insertion of 1 amino acid(s) of the SPTA1 protein (p.Leu155dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757679761, gnomAD 0.09%). This variant has been observed in individuals with autosomal dominant hereditary elliptocytosis and autosomal recessive hereditary pyropoikilocytosis (PMID: 1642244, 2567189, 2794061, 3922449, 8790144, 8857939, 30393954). It has also been observed to segregate with disease in related individuals. This variant is also known as dupL154 and duplication of codon 154. ClinVar contains an entry for this variant (Variation ID: 12847). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SPTA1 function (PMID: 3922449). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000013700	SCV002500695	pathogenic	Elliptocytosis 2	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: SPTA1 c.460_462dupTTG (p.Leu155dup) results in an in-frame duplication that is predicted to duplicate 1 amino acid into the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 249160 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. c.460_462dupTTG (also described as Sp alpha[I/65] and as dupL154) has been reported in the literature in multiple heterozygous individuals, particularly of African descent, affected with hereditary elliptocytosis (e.g. Lawler_1985, Marchesi_1987, Roux_1989, Glele-Kakai_1996, Niss_2016) and in some compound heterozygous individuals affected with hereditary pyropoikilocytosis (e.g. Niss_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence revealed a decrease of the alpha l domain of spectrin and presence of an atypical peptide and also, impaired ability to undergo self association to form tetramers and higher oligomers (Lawler_1985, Marchesi_1987). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics	RCV000598724	SCV002817230	likely pathogenic	not provided	2020-09-11	criteria provided, single submitter	clinical testing	This variant, also referred to as alpha I-65, is enriched in individuals with hereditary elliptocytosis (HE) as compared to the general population (PMID: 8857939, 2567189, 30393954, 32623341). The clinical presentation of HE in individuals who have this variant in the heterozygous sate is typically characterized by mild hemolytic anemia and abnormally-shaped red blood cells. The clinical presentation is more severe when this variant is compound heterozygous with a pathogenic SPTA1 variant. This variant has also been reported to be a modifier of sickle cell anemia (PMID: 2567189, 30393954, 32623341). The frequency of this variant in the general population is uninformative but consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
CeGaT Center for Human Genetics Tuebingen	RCV000598724	SCV004009893	pathogenic	not provided	2023-05-01	criteria provided, single submitter	clinical testing	SPTA1: PM3:Very Strong, PM1, PM2, PP1:Moderate, PS3:Moderate, PM4:Supporting, PP4
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000013700	SCV004121694	pathogenic	Elliptocytosis 2	2023-11-13	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000013700	SCV004805265	pathogenic	Elliptocytosis 2	2024-03-25	criteria provided, single submitter	research
OMIM	RCV000013700	SCV000033947	pathogenic	Elliptocytosis 2	1992-08-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737148	SCV005366678	pathogenic	SPTA1-related disorder	2024-04-19	no assertion criteria provided	clinical testing	The SPTA1 c.460_462dupTTG variant is predicted to result in an in-frame duplication (p.Leu155dup). This variant has been reported to be causative for hereditary elliptocytosis (Roux et al. 1989. PubMed ID: 2567189; Andolfo et al. 2021. PubMed ID: 34201899; Risinger et al. 2018. PubMed ID: 30393954). This variant is reported in 0.095% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.