The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in at least nine individuals affected with either elliptocytosis or hereditary pyropoikilocytosis (Costa 2005, Dalla Venezia 1993, Gallagher 1992, Glele-Kakai 1996). This variant is also reported in ClinVar (Variation ID: 12857). In vitro functional analyses demonstrate reduced protein folding and dimerization (Randles 2013). This variant is found in the African / African-American population with an allele frequency of 0.07% (52/75,030 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Based on available information, this variant is considered to be pathogenic. REFERENCES Costa DB et al. A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. Blood. 2005 Dec 15. PMID: 16150946 Dalla Venezia N et al. An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. Hum Genet. 1993 Feb. PMID: 8444470 Gallagher PG et al. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar. PMID: 1541680 Glele-Kakai C et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol. 1996 Oct. PMID: 8857939 Randles LG et al. Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. FEBS J. 2013 Feb. PMID: 23241237
ClinVar Genomic variation as it relates to human health
NM_003126.4(SPTA1):c.620T>C (p.Leu207Pro)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(2); Likely pathogenic(2); Uncertain significance(1)
5 out of 7 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
7
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003126.4(SPTA1):c.620T>C (p.Leu207Pro)
Variation ID: 12857 Accession: VCV000012857.29
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q23.1 1: 158680641 (GRCh38) [ NCBI UCSC ] 1: 158650431 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 20, 2015 Apr 13, 2025 Apr 8, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003126.4:c.620T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003117.2:p.Leu207Pro missense NC_000001.11:g.158680641A>G NC_000001.10:g.158650431A>G NG_011474.1:g.11076T>C LRG_1131:g.11076T>C P02549:p.Leu207Pro - Protein change
- L207P
- Other names
- -
- Canonical SPDI
- NC_000001.11:158680640:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00060 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00019
The Genome Aggregation Database (gnomAD) 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00014
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00078
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SPTA1 | - | - |
GRCh38 GRCh37 |
1167 | 1233 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Dec 15, 2005 | RCV000013714.32 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 15, 2005 | RCV000013715.31 | |
| Conflicting classifications of pathogenicity (5) |
criteria provided, conflicting classifications
|
Apr 8, 2025 | RCV001509084.34 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Aug 31, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023642.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 03, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001477768.2
First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024 |
Comment:
The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in … (more)
The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in at least nine individuals affected with either elliptocytosis or hereditary pyropoikilocytosis (Costa 2005, Dalla Venezia 1993, Gallagher 1992, Glele-Kakai 1996). This variant is also reported in ClinVar (Variation ID: 12857). In vitro functional analyses demonstrate reduced protein folding and dimerization (Randles 2013). This variant is found in the African / African-American population with an allele frequency of 0.07% (52/75,030 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Based on available information, this variant is considered to be pathogenic. REFERENCES Costa DB et al. A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. Blood. 2005 Dec 15. PMID: 16150946 Dalla Venezia N et al. An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. Hum Genet. 1993 Feb. PMID: 8444470 Gallagher PG et al. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar. PMID: 1541680 Glele-Kakai C et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol. 1996 Oct. PMID: 8857939 Randles LG et al. Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. FEBS J. 2013 Feb. PMID: 23241237 (less)
|
|
|
Pathogenic
(Jul 11, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001715607.4
First in ClinVar: Jun 15, 2021 Last updated: Dec 28, 2024 |
|
|
|
Uncertain significance
(Jan 20, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003523882.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). This variant is present in population databases (rs121918643, gnomAD 0.08%). This missense change has been observed in individual(s) with spherocytosis or pyropoikilocytosis (PMID: 1541680, 8068958, 8444470, 8857939, 18815189). ClinVar contains an entry for this variant (Variation ID: 12857). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPTA1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Likely pathogenic
(Apr 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001770621.3
First in ClinVar: Aug 07, 2021 Last updated: Apr 13, 2025 |
Comment:
Often seen in cis with the common alpha-LELY allele (PMID: 8068958, 18815189); Also known as spectrin St Louis (PMID: 8068958); In silico analysis supports that … (more)
Often seen in cis with the common alpha-LELY allele (PMID: 8068958, 18815189); Also known as spectrin St Louis (PMID: 8068958); 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: 23241237, 8857939, 1541680, 8444470, 18815189, 16150946, 8068958, 8844207, 16730867) (less)
|
|
|
Pathogenic
(Dec 15, 2005)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
PYROPOIKILOCYTOSIS, HEREDITARY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033961.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 20, 2015 |
Comment on evidence:
In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported … (more)
In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported by Zarkowsky et al. (1975), Gallagher et al. (1992) found the alpha-I/46-50a peptide after limited tryptic digestion of spectrin. Further studies identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Dalla Venezia et al. (1993) found the leu207-to-pro mutation in a Moroccan family in both homozygous and heterozygous states. The mutated allele carried, in cis, the common alpha-V/41 polymorphism, which is associated with a low expression level. Dalla Venezia et al. (1993) suggested that the cis combination of an HE mutation and the alpha-V/41 polymorphism accounts for the low expression of the abnormal allele in the heterozygous state. In the original family of Zarkowsky et al. (1975), the L207P mutation was in compound heterozygous state with an SPTA1 allele associated with a defect in alpha-spectrin production. By analysis of reticulocyte alpha-spectrin cDNA from 1 of the original HPP patients, Costa et al. (2005) identified a G-to-A transition (182860.0024) at position +5 of the donor splice site of intron 22 of the SPTA1 gene, resulting in insertion of intronic fragments and an in-frame premature termination codon. Following gene transfer of the IVS22+5 mutation into tissue culture cells, there was complete absence of normally spliced SPTA1 gene transcript. (less)
|
|
|
Pathogenic
(Dec 15, 2005)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
ELLIPTOCYTOSIS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033962.2
First in ClinVar: Apr 04, 2013 Last updated: Nov 20, 2015 |
Comment on evidence:
In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported … (more)
In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported by Zarkowsky et al. (1975), Gallagher et al. (1992) found the alpha-I/46-50a peptide after limited tryptic digestion of spectrin. Further studies identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Dalla Venezia et al. (1993) found the leu207-to-pro mutation in a Moroccan family in both homozygous and heterozygous states. The mutated allele carried, in cis, the common alpha-V/41 polymorphism, which is associated with a low expression level. Dalla Venezia et al. (1993) suggested that the cis combination of an HE mutation and the alpha-V/41 polymorphism accounts for the low expression of the abnormal allele in the heterozygous state. In the original family of Zarkowsky et al. (1975), the L207P mutation was in compound heterozygous state with an SPTA1 allele associated with a defect in alpha-spectrin production. By analysis of reticulocyte alpha-spectrin cDNA from 1 of the original HPP patients, Costa et al. (2005) identified a G-to-A transition (182860.0024) at position +5 of the donor splice site of intron 22 of the SPTA1 gene, resulting in insertion of intronic fragments and an in-frame premature termination codon. Following gene transfer of the IVS22+5 mutation into tissue culture cells, there was complete absence of normally spliced SPTA1 gene transcript. (less)
|
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). This variant is present in population databases (rs121918643, gnomAD 0.08%). This missense change has been observed in individual(s) with spherocytosis or pyropoikilocytosis (PMID: 1541680, 8068958, 8444470, 8857939, 18815189). ClinVar contains an entry for this variant (Variation ID: 12857). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPTA1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Often seen in cis with the common alpha-LELY allele (PMID: 8068958, 18815189); Also known as spectrin St Louis (PMID: 8068958); 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: 23241237, 8857939, 1541680, 8444470, 18815189, 16150946, 8068958, 8844207, 16730867)
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in at least nine individuals affected with either elliptocytosis or hereditary pyropoikilocytosis (Costa 2005, Dalla Venezia 1993, Gallagher 1992, Glele-Kakai 1996). This variant is also reported in ClinVar (Variation ID: 12857). In vitro functional analyses demonstrate reduced protein folding and dimerization (Randles 2013). This variant is found in the African / African-American population with an allele frequency of 0.07% (52/75,030 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Based on available information, this variant is considered to be pathogenic. REFERENCES Costa DB et al. A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. Blood. 2005 Dec 15. PMID: 16150946 Dalla Venezia N et al. An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. Hum Genet. 1993 Feb. PMID: 8444470 Gallagher PG et al. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar. PMID: 1541680 Glele-Kakai C et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol. 1996 Oct. PMID: 8857939 Randles LG et al. Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. FEBS J. 2013 Feb. PMID: 23241237
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). This variant is present in population databases (rs121918643, gnomAD 0.08%). This missense change has been observed in individual(s) with spherocytosis or pyropoikilocytosis (PMID: 1541680, 8068958, 8444470, 8857939, 18815189). ClinVar contains an entry for this variant (Variation ID: 12857). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SPTA1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Often seen in cis with the common alpha-LELY allele (PMID: 8068958, 18815189); Also known as spectrin St Louis (PMID: 8068958); 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: 23241237, 8857939, 1541680, 8444470, 18815189, 16150946, 8068958, 8844207, 16730867)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Nonsense mutations of the alpha-spectrin gene in hereditary pyropoikilocytosis. | Tolpinrud W | Haematologica | 2008 | PMID: 18815189 |
| A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. | Costa DB | Blood | 2005 | PMID: 16150946 |
| Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. | Glele-Kakai C | British journal of haematology | 1996 | PMID: 8857939 |
| Spectrin St Louis and the alpha LELY allele. | Gallagher PG | Blood | 1994 | PMID: 8068958 |
| An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. | Dalla Venezia N | Human genetics | 1993 | PMID: 8444470 |
| A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. | Gallagher PG | The Journal of clinical investigation | 1992 | PMID: 1541680 |
| A congenital haemolytic anaemia with thermal sensitivity of the erythrocyte membrane. | Zarkowsky HS | British journal of haematology | 1975 | PMID: 1191563 |
Text-mined citations for rs121918643 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated May 17, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.