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NM_006415.4(SPTLC1):c.58G>T (p.Ala20Ser) AND Neuropathy, hereditary sensory and autonomic, type 1A

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 2, 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:
RCV004594033.1

Allele description [Variation Report for NM_006415.4(SPTLC1):c.58G>T (p.Ala20Ser)]

NM_006415.4(SPTLC1):c.58G>T (p.Ala20Ser)

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.58G>T (p.Ala20Ser)
HGVS:
  • NC_000009.12:g.92112562C>A
  • NG_007950.1:g.7847G>T
  • NM_001281303.2:c.58G>T
  • NM_001368272.1:c.-442G>T
  • NM_001368273.1:c.-408G>T
  • NM_006415.4:c.58G>TMANE SELECT
  • NM_178324.3:c.58G>T
  • NP_001268232.1:p.Ala20Ser
  • NP_006406.1:p.Ala20Ser
  • NP_006406.1:p.Ala20Ser
  • NP_847894.1:p.Ala20Ser
  • LRG_272t1:c.58G>T
  • LRG_272:g.7847G>T
  • LRG_272p1:p.Ala20Ser
  • NC_000009.11:g.94874844C>A
  • NM_006415.2:c.58G>T
  • NM_006415.3:c.58G>T
  • c.58G-T, EX2DEL
Protein change:
A20S
Links:
OMIM: 605712.0011; dbSNP: rs879254294
NCBI 1000 Genomes Browser:
rs879254294
Molecular consequence:
  • NM_001368272.1:c.-442G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001368273.1:c.-408G>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281303.2:c.58G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006415.4:c.58G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_178324.3:c.58G>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
exon loss [Variation Ontology: 0381]

Condition(s)

Name:
Neuropathy, hereditary sensory and autonomic, type 1A (HSAN1A)
Synonyms:
NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IA; HSAN IA; HSN IA; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008086; MedGen: C5235211; OMIM: 162400

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005086412Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 2, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

Mohassel P, Donkervoort S, Lone MA, Nalls M, Gable K, Gupta SD, Foley AR, Hu Y, Saute JAM, Moreira AL, Kok F, Introna A, Logroscino G, Grunseich C, Nickolls AR, Pourshafie N, Neuhaus SB, Saade D, Gangfuß A, Kölbel H, Piccus Z, Le Pichon CE, et al.

Nat Med. 2021 Jul;27(7):1197-1204. doi: 10.1038/s41591-021-01346-1. Epub 2021 May 31.

PubMed [citation]
PMID:
34059824
PMCID:
PMC9309980

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086412.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This missense variant results in complete skipping of exon 2 of the SPTLC1 protein (PMID: 34059824). (SP) 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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in three individuals with juvenile amyotrophic lateral sclerosis (Johnson, JO. et al. (2020) PriPrint, PMID: 34059824). It has also been reported as VUS once in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional data demonstrated abnormal SPTLC1 function by measuring sphingolipids extracted from plasma (Johnson, JO. et al. (2020) PriPrint). (SP) 1102 - Strong phenotype match for this individual. (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 4, 2024