NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr) AND Hereditary sensory and autonomic neuropathy type 1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 17, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000795948.10

Allele description [Variation Report for NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr)]

NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr)

Gene:

SPTLC1:serine palmitoyltransferase long chain base subunit 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.31

Genomic location:

Preferred name:

NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr)

HGVS:

NC_000009.12:g.92047261G>T
NG_007950.1:g.73148C>A
NM_001281303.2:c.992C>A
NM_001368272.1:c.626C>A
NM_001368273.1:c.527C>A
NM_006415.4:c.992C>AMANE SELECT
NP_001268232.1:p.Ser331Tyr
NP_001355201.1:p.Ser209Tyr
NP_001355202.1:p.Ser176Tyr
NP_006406.1:p.Ser331Tyr
LRG_272t1:c.992C>A
LRG_272:g.73148C>A
NC_000009.11:g.94809543G>T
NM_006415.2:c.992C>A
NM_006415.3:c.992C>A

Note:

NCBI staff developed the HGVS expression for this allele given that the only substitution that could generate S331Y is C>A. The paper by Auer-Grumbach et al., 2013 ((PubMed 23454272) described this as c.992G->T.

Protein change:

S176Y; SER331TYR

Links:

OMIM: 605712.0007; dbSNP: rs267607087

NCBI 1000 Genomes Browser:

rs267607087

Molecular consequence:

NM_001281303.2:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368272.1:c.626C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368273.1:c.527C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006415.4:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary sensory and autonomic neuropathy type 1 (HSAN1)
Synonyms:: HSAN 1; Neuropathy hereditary sensory radicular, autosomal dominant; Hereditary sensory neuropathy type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018213; MedGen: C0020071; Orphanet: 36386

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000935430	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19651702, 21618344, 24247255, 26681808, 23454272, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000935430

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.

Rotthier A, Baets J, De Vriendt E, Jacobs A, Auer-Grumbach M, Lévy N, Bonello-Palot N, Kilic SS, Weis J, Nascimento A, Swinkels M, Kruyt MC, Jordanova A, De Jonghe P, Timmerman V.

Brain. 2009 Oct;132(Pt 10):2699-711. doi: 10.1093/brain/awp198. Epub 2009 Aug 3.

PubMed [citation]

PMID:: 19651702
PMCID:: PMC2759337

Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I.

Rotthier A, Penno A, Rautenstrauss B, Auer-Grumbach M, Stettner GM, Asselbergh B, Van Hoof K, Sticht H, Lévy N, Timmerman V, Hornemann T, Janssens K.

Hum Mutat. 2011 Jun;32(6):E2211-25. doi: 10.1002/humu.21481. Epub 2011 Feb 24.

PubMed [citation]

PMID:: 21618344

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000935430.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser331 amino acid residue in SPTLC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19651702, 21618344, 24247255). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 26681808). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372788). This missense change has been observed in individual(s) with SPTCL1-related disease (PMID: 23454272). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 331 of the SPTLC1 protein (p.Ser331Tyr).

#	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

Last Updated: Feb 25, 2025

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