NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp) AND Neuropathy, hereditary sensory and autonomic, type 1A

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jul 20, 2021
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:: RCV001249799.13

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

NCBI 1000 Genomes Browser:

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)

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025244	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 2001)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 11242114, 26681808, 34986032
SCV000058074	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000894482	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001870324	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI WGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 15, 2020)	maternal	research	PubMed (1) [See all records that cite this PMID]
SCV002047702	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Jul 20, 2021)	germline	clinical testing	Citation Link

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	1	not provided	research
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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

HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.

Bode H, Bourquin F, Suriyanarayanan S, Wei Y, Alecu I, Othman A, Von Eckardstein A, Hornemann T.

Hum Mol Genet. 2016 Mar 1;25(5):853-65. doi: 10.1093/hmg/ddv611. Epub 2015 Dec 17.

PubMed [citation]

PMID:: 26681808

See all PubMed Citations (5)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000025244.4

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

Description

In 2 families of Australian/Scottish and Australian/English extraction with hereditary sensory neuropathy type I (HSAN1A; 162400), Dawkins et al. (2001) identified a T-to-A transversion at nucleotide 431 in exon 6 of the SPTLC1 gene, resulting in a valine-to-aspartic acid substitution at codon 144 (V144D). Valine-144 of SPTLC1 is conserved in human, mouse, Drosophila, and yeast.

Based on in vitro functional enzymatic studies, Bode et al. (2016) suggested that the V144D variant may not be pathogenic. The variant did not show significantly increased activity with alanine over serine and did not form significant amounts of neurotoxic 1-deoxySL compounds compared to the wildtype enzyme.

Antony et al. (2022) found that expression of the SPTLC1 V144D mutant increased cytoplasmic Ca(2+) but decreased mitochondrial Ca(2+) in SH-SY5Y cells, leading to activation of the Ca(2+)-dependent protease systems, calpain (see 114220) and proteasome (see 176843). Moreover, the calpain substrates MAP2 (157130) and tau (MAPT; 157140) were significantly decreased in cells expressing V144D. Altered microtubule binding of motor proteins and decreased mitochondrial transport velocities were also observed in cells overexpressing V144D.

#	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 GeneReviews, SCV000058074.3

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

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

From Fulgent Genetics, Fulgent Genetics, SCV000894482.1

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

#	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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - AGHI WGS, SCV001870324.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

Description

ACMG codes: PS3, PP3, PP5

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002047702.1

#	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) is reported in the literature in several individuals affected with hereditary sensory neuropathy (Dawkins 2001, Ho 2018). This variant is found on only two chromosomes in the Genome Aggregation Database (2/250360 alleles), indicating it is not a common polymorphism. The valine at codon 144 is highly conserved, and 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 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 and Jerath. 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 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 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 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.

#	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: Oct 13, 2024

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