rs119482081

Positions:

• chr9-92080045-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006415.4(SPTLC1):​c.398G>A​(p.Cys133Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C133R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTLC1 NM_006415.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 5.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-92080046-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 9-92080045-C-T is Pathogenic according to our data. Variant chr9-92080045-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92080045-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC1	NM_006415.4	c.398G>A	p.Cys133Tyr	missense_variant	5/15	ENST00000262554.7	NP_006406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7	c.398G>A	p.Cys133Tyr	missense_variant	5/15	1	NM_006415.4	ENSP00000262554	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1A Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2021

The c.398G>A (p.C133Y) alteration is located in exon 5 (coding exon 5) of the SPTLC1 gene. This alteration results from a G to A substitution at nucleotide position 398, causing the cysteine (C) at amino acid position 133 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to segregate with disease in multiple families with hereditary sensory neuropathy and is one of the most common mutations in SPTLC1 (Bejaoui 2001; Dawkins, 2001; Geraldes 2004; Fridman, 2015). This amino acid position is highly conserved in available vertebrate species. Experimental studies showed that this alteration results in significantly increased synthesis of 1-deoxy-sphingolipids and that accumulation of this neurotoxic metabolite is the pathological mechanism in HSAN1 (Bejaoui, 2001; Penno, 2010; Bode, 2016). In another study, in vitro overexpression of the C133Y mutant resulted in a 50% reduction in serine palmitoyltransferase (SPT) activity (Hornemann, 2009). Bejaoui, et al., 2002, showed that this mutation confers dominant negative effects on SPT activity in various cell types including cultured lymphocytes from HSN1 patients. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary sensory and autonomic neuropathy type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 07, 2020

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects the function of the SPTLC1 protein (PMID: 12417569, 19132419, 20097765, 26681808). This variant has been observed to segregate with hereditary sensory neuropathy in several families (PMID: 11242106, 11242114, 15546589). ClinVar contains an entry for this variant (Variation ID: 4800). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 133 of the SPTLC1 protein (p.Cys133Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Inherited Neuropathy Consortium

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.84		Gain of solvent accessibility (P = 0.1116);Gain of solvent accessibility (P = 0.1116);
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs119482081; hg19: chr9-94842327;