rs119482083

Positions:

chr9-92068095-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_006415.4(SPTLC1):c.431T>A(p.Val144Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SPTLC1
NM_006415.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 9.03

Variant links:

Genes affected

SPTLC1 (HGNC:11277): (serine palmitoyltransferase long chain base subunit 1) This gene encodes a member of the class-II pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is the long chain base subunit 1 of serine palmitoyltransferase. Serine palmitoyltransferase converts L-serine and palmitoyl-CoA to 3-oxosphinganine with pyridoxal 5'-phosphate and is the key enzyme in sphingolipid biosynthesis. Mutations in this gene were identified in patients with hereditary sensory neuropathy type 1. Alternatively spliced variants encoding different isoforms have been identified. Pseudogenes of this gene have been defined on chromosomes 1, 6, 10, and 13. [provided by RefSeq, Jul 2013]

SPTLC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 9-92068095-A-T is Pathogenic according to our data. Variant chr9-92068095-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92068095-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC1	NM_006415.4 linkuse as main transcript	c.431T>A	p.Val144Asp	missense_variant	6/15	ENST00000262554.7	NP_006406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7 linkuse as main transcript	c.431T>A	p.Val144Asp	missense_variant	6/15	1	NM_006415.4	ENSP00000262554	P1	O15269-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250360

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461462

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1A

Pathogenic:4Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 20, 2021	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. -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	May 15, 2020	ACMG codes: PS3, PP3, PP5 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 22, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2022	Reported in multiple individuals with hereditary neuropathy previously tested at at GeneDx and in the published literature (Dawkins et al., 2001; Vogt et al., 2020); Protein expression studies show that p.(V144D) is associated with changes to the mitochondrial proteins (Stimpson et al., 2015); additionally, p.(V144D) is associated with structural changes to the mitochondria including electron dense and enlarged cristae (Myers et al., 2014).; Published functional studies demonstrate a damaging effect on SPT activity and calcium regulation (Antony et al., 2022; Hornemann et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30420926, 26681808, 25584079, 33497257, 34986032, 30778062, 34337561, 32730653, 15546589, 26395456, 24175284, 23454272, 30762923, 20920666, 24673574, 19132419, 32195206, 32399692, 20301564, 18348718, 25947379, 35895683, 35181405, 35904184, 35899376, 11242114) -

Charcot-Marie-Tooth disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

SPTLC1-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2024

The SPTLC1 c.431T>A variant is predicted to result in the amino acid substitution p.Val144Asp. This variant has been reported in multiple individuals with hereditary sensory neuropathy (Table 2, Dawkins et al. 2001. PubMed ID: 11242114; Ho and Jerath. 2018. PubMed ID: 30420926; Table 1, Vogt et al. 2020. PubMed ID: 32399692). This variant is reported in 0.0018% of alleles in individuals of European (non-Finnish) descent in gnomAD. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein and negatively regulates the BiP pathway (Hornemann et al. 2009. PubMed ID: 19132419; Myers et al. 2014. PubMed ID: 24673574). This variant is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4801/). In summary, this variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The p.V144D variant (also known as c.431T>A), located in coding exon 6 of the SPTLC1 gene, results from a T to A substitution at nucleotide position 431. The valine at codon 144 is replaced by aspartic acid, an amino acid with highly dissimilar properties. The p.V144D alteration has been reported to co-segregate with disease in several families with sensory neuropathy (Nicholson GA et al. Nat. Genet., 1996 May;13:101-4; Dawkins JL et al. Nat. Genet., 2001 Mar;27:309-12; Ho KWD et al. Case Rep Genet, 2018 Oct;2018:1898151; Vogt B et al. J Neurol, 2020 Sep;267:2648-2654). The functional studies of V144D show an impact on mitochondrial structure and protein expression; however, a direct link to the mechanism of pathology is not clear and enzymatic activity studies are conflicting (Hornemann T et al. Neurogenetics, 2009 Apr;10:135-43; Myers SJ et al. DNA Cell Biol., 2014 Jul;33:399-407; Stimpson SE et al. J Chem Biol, 2015 Jan;8:25-35; Bode H et al. Hum. Mol. Genet., 2016 Mar;25:853-65). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary sensory and autonomic neuropathy type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 144 of the SPTLC1 protein (p.Val144Asp). This variant is present in population databases (rs119482083, gnomAD 0.002%). This missense change has been observed in individuals with hereditary sensory neuropathy (PMID: 11242114; Invitae). ClinVar contains an entry for this variant (Variation ID: 4801). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPTLC1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 11242114, 19132419, 24673574, 25584079, 26681808). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.93

MPC

1.4

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over