9-92047261-G-T

Position:

• chr9-92047261-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_006415.4(SPTLC1):​c.992C>A​(p.Ser331Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. S331F) 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:4 U:1
• Conservation: PhyloP100: 9.66

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-92047261-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 9-92047261-G-T is Pathogenic according to our data. Variant chr9-92047261-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 372788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC1	NM_006415.4	c.992C>A	p.Ser331Tyr	missense_variant	11/15	ENST00000262554.7	NP_006406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC1	ENST00000262554.7	c.992C>A	p.Ser331Tyr	missense_variant	11/15	1	NM_006415.4	ENSP00000262554.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type IA, severe Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 14, 2023

- -

Hereditary sensory and autonomic neuropathy type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser331 amino acid residue in SPTLC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19651702, 21618344, 24247255). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SPTLC1 function (PMID: 26681808). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 372788). This missense change has been observed in individual(s) with SPTCL1-related disease (PMID: 23454272). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 331 of the SPTLC1 protein (p.Ser331Tyr). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 04, 2016

The S331Y pathogenic variant in the SPTLC1 gene has been reported previously as a heterozygous de novo variant in an individual with a diagnosis of HSN1A who presented with normal early development followed by failure to thrive in childhood, abnormal gait, frequent falls, and moderate hand tremor. Later in childhood, general muscle hypotrophy and hypotonia with pronounced limb weakness, growth retardation, fasciculations, joint hypermobility, juvenile cataracts, foot burns and scars and prominent sensory disturbances were noted (Auer-Grumbach et al., 2013). The S331Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S331Y variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies show a significant reduction in the canonical SPT activity and a significant increase of 1-deoxy-sphinganin formation in HEK293 cells compared to wild type cells (Auer-Grumbach et al., 2013; Bode et al., 2016). A missense variant at the same residue (S331F) has also been reported in multiple individuals with severe and early onset HSN1A (Rotthier et al., 2011; Rotthier et al., 2009). Therefore, we interpret S331Y as a pathogenic variant. -

Amyotrophic lateral sclerosis 27, juvenile Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 14, 2023

- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.45	P
Vest4		0.93
MutPred		0.53		Loss of glycosylation at S331 (P = 0.0686);
MVP		0.85
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267607087; hg19: chr9-94809543;