NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 18, 2025
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:: RCV000235837.11

Allele description [Variation Report for NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)]

NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)

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.431T>A (p.Val144Asp)

HGVS:

NC_000009.12:g.92068095A>T
NG_007950.1:g.52314T>A
NM_001281303.2:c.431T>A
NM_001368272.1:c.65T>A
NM_001368273.1:c.-35T>A
NM_006415.4:c.431T>AMANE SELECT
NP_001268232.1:p.Val144Asp
NP_001355201.1:p.Val22Asp
NP_006406.1:p.Val144Asp
LRG_272t1:c.431T>A
LRG_272:g.52314T>A
LRG_272p1:p.Val144Asp
NC_000009.11:g.94830377A>T
NM_006415.2:c.431T>A
NM_006415.3:c.431T>A
O15269:p.Val144Asp

Protein change:

V144D; VAL144ASP

Links:

UniProtKB: O15269#VAR_011394; OMIM: 605712.0003; dbSNP: rs119482083

Molecular consequence:

NM_001368273.1:c.-35T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001281303.2:c.431T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001368272.1:c.65T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006415.4:c.431T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000293136	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 18, 2025)	germline	clinical testing	Citation Link,
SCV002047702	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely Pathogenic (Jul 8, 2025)	germline	clinical testing	Citation Link,
SCV004229214	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 22, 2023)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11242114, 19132419, 25584079, 32399692, 30420926, 26681808, 8673084, 27164712, 24711860, 20097765, 11781309, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000293136

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 18, 2025)

germline

clinical testing

Citation Link,

SCV002047702

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Likely Pathogenic
(Jul 8, 2025)

germline

clinical testing

Citation Link,

SCV004229214

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Pathogenic
(Jun 22, 2023)

unknown

clinical testing

PubMed (12)
[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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.

Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA.

Nat Genet. 2001 Mar;27(3):309-12.

PubMed [citation]

PMID:: 11242114

A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.

Hornemann T, Penno A, Richard S, Nicholson G, van Dijk FS, Rotthier A, Timmerman V, von Eckardstein A.

Neurogenetics. 2009 Apr;10(2):135-43. doi: 10.1007/s10048-008-0168-7. Epub 2009 Jan 9.

PubMed [citation]

PMID:: 19132419

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000293136.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Reported in multiple individuals with hereditary neuropathy previously tested at GeneDx and in the published literature (PMID: 11242114, 32399692, 27164712); Protein expression studies show that p.(V144D) is associated with changes to the mitochondrial proteins and with structural changes to the mitochondria including electron dense and enlarged cristae (PMID: 24673574, 25584079); Published functional studies demonstrate a damaging effect on SPT activity and calcium regulation (PMID: 19132419, 34986032); 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: 30420926, 26681808, 25584079, 33497257, 34986032, 30778062, 34337561, 32730653, 15546589, 26395456, 24175284, 23454272, 30762923, 20920666, 32195206, 32399692, 20301564, 18348718, 25947379, 35895683, 35181405, 35904184, 35899376, 24711860, 20097765, 11781309, 8673084, 37509182, 36997154, 39901509, 24673574, 19132419, 11242114, 27164712)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002047702.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The SPTLC1 c.431T>A; p.Val144Asp variant (rs119482083; ClinVar Variation ID: 4801) is reported in the literature in several individuals affected with hereditary sensory neuropathy (Dawkins 2001, Ho 2018, Vogt 2020). This variant is found on only two chromosomes (2/250360 alleles) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.921). Consistent with predictions, functional studies suggest the variant protein has reduced enzymatic activity and is associated with mitochondrial alterations (Hornemann 2009, Myers 2014, Stimpson 2014). Based on available information, this variant is considered to be likely pathogenic. References: Dawkins JL et al. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001 Mar;27(3):309-12. PMID 11242114. Ho KWD and Jerath NU. V144D Mutation of SPTLC1 Can Present with Both Painful and Painless Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I. Case Rep Genet. 2018 Oct 18;2018:1898151. PMID: 30420926. Hornemann T et al., A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated. Neurogenetics. 2009 Apr;10(2):135-43. PMID 19132419. Myers SJ et al., Mutations in the SPTLC1 protein cause mitochondrial structural abnormalities and endoplasmic reticulum stress in lymphoblasts. DNA Cell Biol. 2014 Jul;33(7):399-407. PMID 24673574. Stimpson SE et al., Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. J Chem Biol. 2014 Nov 14;8(1):25-35. PMID 25584079. Vogt B et al. Screening for genetic mutations in patients with neuropathy without definite etiology is useful. J Neurol. 2020 Sep;267(9):2648-2654. PMID: 32399692.

#	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 Athena Diagnostics, SCV004229214.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals, and segregates with disease in at least one family with HSAN. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11781309, 19132419)

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

Last Updated: Mar 28, 2026

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