NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe) AND Neuropathy, hereditary sensory and autonomic, type 1C

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000796505.15

Allele description [Variation Report for NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)]

NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)

Gene:

SPTLC2:serine palmitoyltransferase long chain base subunit 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q24.3

Genomic location:

Preferred name:

NM_004863.4(SPTLC2):c.1151C>T (p.Ser384Phe)

HGVS:

NC_000014.9:g.77555325G>A
NG_028282.1:g.66443C>T
NM_004863.4:c.1151C>TMANE SELECT
NP_004854.1:p.Ser384Phe
NP_004854.1:p.Ser384Phe
LRG_371t1:c.1151C>T
LRG_371:g.66443C>T
LRG_371p1:p.Ser384Phe
NC_000014.8:g.78021668G>A
NM_004863.3:c.1151C>T
p.Ser384Phe

Protein change:

S384F; SER384PHE

Links:

OMIM: 605713.0005; dbSNP: rs1594986869

NCBI 1000 Genomes Browser:

rs1594986869

Molecular consequence:

NM_004863.4:c.1151C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuropathy, hereditary sensory and autonomic, type 1C
Synonyms:: HSAN IC; HSN IC; Hereditary sensory and autonomic neuropathy type IC
Identifiers:: MONDO: MONDO:0013337; MedGen: C3150896; Orphanet: 36386; OMIM: 613640

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000936023	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 7, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26681808, 25567748, 29184351, 28492532
SCV000998542	OMIM	no assertion criteria provided	Pathogenic (Nov 4, 2019)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 25567748, 31509666, 30866134
SCV002503609	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 17081983, 25567748, 26681808, 30866134, 30995999, 31509666, 25741868
SCV005086560	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25567748, 26681808, 31509666, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinico-Electrophysiological and Genetic Overlaps and Magnetic Resonance Imaging Findings in Charcot-Marie- Tooth Disease: A Pilot Study from Western India.

Khadilkar SV, Patil ND, Kadam ND, Mansukhani KA, Patel BA.

Ann Indian Acad Neurol. 2017 Oct-Dec;20(4):425-429. doi: 10.4103/aian.AIAN_316_17.

PubMed [citation]

PMID:: 29184351
PMCID:: PMC5682752

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936023.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV000998542.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV002503609.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086560.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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