PS3, PS4_moderate, PM1, PM2, PP3, PP1
ClinVar Genomic variation as it relates to human health
NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)
Germline
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.
(6)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)
Variation ID: 637418 Accession: VCV000637418.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q24.3 14: 77555325 (GRCh38) [ NCBI UCSC ] 14: 78021668 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Jul 27, 2019 Jul 23, 2024 Dec 21, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004863.4:c.1151C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004854.1:p.Ser384Phe missense NC_000014.9:g.77555325G>A NC_000014.8:g.78021668G>A NG_028282.1:g.66443C>T LRG_371:g.66443C>T LRG_371t1:c.1151C>T LRG_371p1:p.Ser384Phe - Protein change
- S384F
- Other names
- -
- Canonical SPDI
- NC_000014.9:77555324:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
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| SPTLC2 | - | - |
GRCh38 GRCh37 |
618 | 644 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000789584.1 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 21, 2023 | RCV000796505.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 26, 2020 | RCV001508368.5 |
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. |
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Pathogenic
(Oct 26, 2020)
|
criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714483.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_moderate, PM1, PM2, PP3, PP1
Number of individuals with the variant: 1
|
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Pathogenic
(May 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Neuropathy, hereditary sensory and autonomic, type 1C
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000936023.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTLC2 protein function (PMID: 25567748, 26681808). This variant … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTLC2 protein function (PMID: 25567748, 26681808). This variant has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 25567748, 29184351). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 637418). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 384 of the SPTLC2 protein (p.Ser384Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. (less)
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Likely pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Neuropathy, hereditary sensory and autonomic, type 1C
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503609.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace serine with phenylalanine at codon 384 of the SPTLC2 protein, p.(Ser384Phe). The serine residue is moderately conserved (100 … (more)
This sequence change is predicted to replace serine with phenylalanine at codon 384 of the SPTLC2 protein, p.(Ser384Phe). The serine residue is moderately conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between serine and phenylalanine. Ser384 is a confirmed phosphorylation site located in the aminotransferase class I/II domain that regulates substrate specificity (PMID: 17081983, 25567748). The variant is absent in a large population cohort (gnomAD v2.1). It has been identified in multiple unrelated individuals diagnosed with hereditary sensory and autonomic neuropathy type 1 with a later age of onset (PMID: 25567748, 30866134, 30995999, 31509666), and segregates with this phenotype in multiple families (PMID: 25567748, 31509666). Patient cells from variant carriers show significantly elevated plasma 1-deoxysphingolipids levels, with unaltered levels of canonical sphingolipids (PMID: 25567748). In vitro functional assays of p.Ser384Phe show increased 1-deoxysphingolipids levels and reduced protein activity (PMID: 25567748, 26681808). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1, PM2, PP1_Moderate, PS3_Supporting,PP3, PP4. (less)
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Pathogenic
(Dec 21, 2023)
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criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory and autonomic, type 1C
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086560.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with neuropathy, hereditary sensory and autonomic, type IC, (MIM#613640). Missense variants in this gene have been proven to result in increased 1-deoxySL levels (PMID: 26681808, PMID: 25567748). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability described (PMID: 25567748). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class I and II domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in several individuals with hereditary sensory and autonomic neuropathy type 1 with/without macular telangiectasia type 2 (ClinVar, PMID: 25567748, PMID: 31509666). (SP) 0901 - This variant has strong evidence for segregation with disease, having segregated in two families with at least seven affected individuals either confirmed to have the variant or are obligate carriers (PMID: 25567748). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000928940.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
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Pathogenic
(Nov 04, 2019)
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no assertion criteria provided
Method: literature only
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NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000998542.2
First in ClinVar: Nov 02, 2019 Last updated: Nov 11, 2019 |
Comment on evidence:
In affected members of 2 unrelated families with hereditary sensory and autonomic neuropathy type IC (HSAN1C; 613640), Ernst et al. (2015) identified a heterozygous c.1151C-T … (more)
In affected members of 2 unrelated families with hereditary sensory and autonomic neuropathy type IC (HSAN1C; 613640), Ernst et al. (2015) identified a heterozygous c.1151C-T transition in the SPTLC2 gene, resulting in a ser384-to-phe (S384F) substitution at a conserved residue in mammals. The mutation segregated with the disorder in the families. The variant was not found in 478 control chromosomes or in the 1000 Genomes Project or ESP65000 databases. Expression of the S384F mutation in HEK293 cells resulted in increased 1-deoxysphingolipids. In a father and son (family 3) with HSAN1C who also had macular telangiectasia type 2, Gantner et al. (2019) identified a heterozygous S384F mutation in the SPTLC2 gene. Functional studies of the variant and studies of patient cells were not performed. In a 52-year-old man with HSAN1C and macular telangiectasia type 2, Triplett et al. (2019) identified a heterozygous S384F mutation in the SPTLC2 gene. The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed, but the patient had elevated plasma levels of 1-deoxySL. (less)
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTLC2 protein function (PMID: 25567748, 26681808). This variant has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 25567748, 29184351). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 637418). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 384 of the SPTLC2 protein (p.Ser384Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine.
Comment:
This sequence change is predicted to replace serine with phenylalanine at codon 384 of the SPTLC2 protein, p.(Ser384Phe). The serine residue is moderately conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between serine and phenylalanine. Ser384 is a confirmed phosphorylation site located in the aminotransferase class I/II domain that regulates substrate specificity (PMID: 17081983, 25567748). The variant is absent in a large population cohort (gnomAD v2.1). It has been identified in multiple unrelated individuals diagnosed with hereditary sensory and autonomic neuropathy type 1 with a later age of onset (PMID: 25567748, 30866134, 30995999, 31509666), and segregates with this phenotype in multiple families (PMID: 25567748, 31509666). Patient cells from variant carriers show significantly elevated plasma 1-deoxysphingolipids levels, with unaltered levels of canonical sphingolipids (PMID: 25567748). In vitro functional assays of p.Ser384Phe show increased 1-deoxysphingolipids levels and reduced protein activity (PMID: 25567748, 26681808). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1, PM2, PP1_Moderate, PS3_Supporting,PP3, PP4.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with neuropathy, hereditary sensory and autonomic, type IC, (MIM#613640). Missense variants in this gene have been proven to result in increased 1-deoxySL levels (PMID: 26681808, PMID: 25567748). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability described (PMID: 25567748). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class I and II domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in several individuals with hereditary sensory and autonomic neuropathy type 1 with/without macular telangiectasia type 2 (ClinVar, PMID: 25567748, PMID: 31509666). (SP) 0901 - This variant has strong evidence for segregation with disease, having segregated in two families with at least seven affected individuals either confirmed to have the variant or are obligate carriers (PMID: 25567748). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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:
PS3, PS4_moderate, PM1, PM2, PP3, PP1
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SPTLC2 protein function (PMID: 25567748, 26681808). This variant has been observed in individual(s) with hereditary sensory and autonomic neuropathy (PMID: 25567748, 29184351). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 637418). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 384 of the SPTLC2 protein (p.Ser384Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine.
Comment:
This sequence change is predicted to replace serine with phenylalanine at codon 384 of the SPTLC2 protein, p.(Ser384Phe). The serine residue is moderately conserved (100 vertebrates, UCSC), and there is a large physicochemical difference between serine and phenylalanine. Ser384 is a confirmed phosphorylation site located in the aminotransferase class I/II domain that regulates substrate specificity (PMID: 17081983, 25567748). The variant is absent in a large population cohort (gnomAD v2.1). It has been identified in multiple unrelated individuals diagnosed with hereditary sensory and autonomic neuropathy type 1 with a later age of onset (PMID: 25567748, 30866134, 30995999, 31509666), and segregates with this phenotype in multiple families (PMID: 25567748, 31509666). Patient cells from variant carriers show significantly elevated plasma 1-deoxysphingolipids levels, with unaltered levels of canonical sphingolipids (PMID: 25567748). In vitro functional assays of p.Ser384Phe show increased 1-deoxysphingolipids levels and reduced protein activity (PMID: 25567748, 26681808). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_Moderate, PM1, PM2, PP1_Moderate, PS3_Supporting,PP3, PP4.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with neuropathy, hereditary sensory and autonomic, type IC, (MIM#613640). Missense variants in this gene have been proven to result in increased 1-deoxySL levels (PMID: 26681808, PMID: 25567748). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, with intrafamilial variability described (PMID: 25567748). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated aminotransferase class I and II domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in several individuals with hereditary sensory and autonomic neuropathy type 1 with/without macular telangiectasia type 2 (ClinVar, PMID: 25567748, PMID: 31509666). (SP) 0901 - This variant has strong evidence for segregation with disease, having segregated in two families with at least seven affected individuals either confirmed to have the variant or are obligate carriers (PMID: 25567748). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Demyelination in hereditary sensory neuropathy type-1C. | Saba S | Annals of clinical and translational neurology | 2020 | PMID: 32730653 |
| Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. | Gantner ML | The New England journal of medicine | 2019 | PMID: 31509666 |
| Development of MRC Centre MRI calf muscle fat fraction protocol as a sensitive outcome measure in Hereditary Sensory Neuropathy Type 1. | Kugathasan U | Journal of neurology, neurosurgery, and psychiatry | 2019 | PMID: 30995999 |
| A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C. | Suriyanarayanan S | Neuromolecular medicine | 2019 | PMID: 30955194 |
| Hereditary sensory and autonomic neuropathy type IC accompanied by upper motor neuron abnormalities and type II juxtafoveal retinal telangiectasias. | Triplett J | Journal of the peripheral nervous system : JPNS | 2019 | PMID: 30866134 |
| Clinico-Electrophysiological and Genetic Overlaps and Magnetic Resonance Imaging Findings in Charcot-Marie- Tooth Disease: A Pilot Study from Western India. | Khadilkar SV | Annals of Indian Academy of Neurology | 2017 | PMID: 29184351 |
| Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. | Dohrn MF | Journal of neurochemistry | 2017 | PMID: 28902413 |
| HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. | Bode H | Human molecular genetics | 2016 | PMID: 26681808 |
| Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity. | Ernst D | Neuromolecular medicine | 2015 | PMID: 25567748 |
| Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. | Olsen JV | Cell | 2006 | PMID: 17081983 |
Text-mined citations for rs1594986869 ...
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 Sep 29, 2024
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.