VCV000802489.13 - ClinVar

NM_006415.4(SPTLC1):c.112CTT[1] (p.Leu39del)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006415.4(SPTLC1):c.112CTT[1] (p.Leu39del)

Variation ID: 802489 Accession: VCV000802489.13

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 9q22.31 9: 92112503-92112505 (GRCh38) [ NCBI UCSC ] 9: 94874785-94874787 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 11, 2020	Oct 26, 2024	Mar 1, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_006415.4:c.112CTT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006406.1:p.Leu39del	inframe deletion
NM_006415.4:c.115_117del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_006415.4:c.115_117delCTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001281303.2:c.112CTT[1]	NP_001268232.1:p.Leu39del	inframe deletion
NM_001368272.1:c.-388CTT[1]		5 prime UTR
NM_001368273.1:c.-354CTT[1]		5 prime UTR
NM_178324.3:c.112CTT[1]	NP_847894.1:p.Leu39del	inframe deletion
NC_000009.12:g.92112503AAG[1]
NC_000009.11:g.94874785AAG[1]
NG_007950.1:g.7901CTT[1]
LRG_272:g.7901CTT[1]
LRG_272t1:c.115_117del

... more HGVS ... less HGVS

Protein change

L39del

Other names

Canonical SPDI

NC_000009.12:92112502:AAGAAG:AAG

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 605712.0010 dbSNP: rs1197928094 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SPTLC1		-	-	GRCh38 GRCh37	434	471

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Neuropathy, hereditary sensory and autonomic, type 1A	Likely pathogenic (2)	criteria provided, single submitter	May 28, 2019	RCV000988188.4
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 15, 2021	RCV001560232.4
Hereditary sensory and autonomic neuropathy type 1	Pathogenic (1)	criteria provided, single submitter	Sep 24, 2021	RCV001858688.4
EMG abnormality Falls Muscle spasm Proximal lower limb amyotrophy Proximal muscle weakness	Likely pathogenic (1)	criteria provided, single submitter	Mar 1, 2022	RCV002468610.4
Amyotrophic lateral sclerosis 27, juvenile	Pathogenic (1)	no assertion criteria provided	Mar 16, 2023	RCV003152613.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Neuropathy, hereditary sensory and autonomic, type 1A Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001137822.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020
Likely pathogenic (Aug 14, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001782597.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Comment: Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; Has … (more) Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34059824) (less)
Likely pathogenic (Mar 01, 2022)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Proximal lower limb amyotrophy Proximal muscle weakness EMG abnormality Falls Muscle spasm (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764914.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Proximal lower limb amyotrophy (present) , Proximal muscle weakness (present) , EMG abnormality (present) , Falls (present) , Muscle spasm (present)
Pathogenic (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003819743.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Sep 24, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary sensory and autonomic neuropathy type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002213359.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 34059824 Comment: For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SPTLC1 function (PMID: 34059824). Algorithms developed to … (more) For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SPTLC1 function (PMID: 34059824). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with juvenile ALS (PMID: 34059824; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This variant, c.115_117del, results in the deletion of 1 amino acid(s) of the SPTLC1 protein (p.Leu39del), but otherwise preserves the integrity of the reading frame. (less)
Pathogenic (Mar 16, 2023)	no assertion criteria provided Method: literature only	AMYOTROPHIC LATERAL SCLEROSIS 27, JUVENILE Affected status: not provided Allele origin: germline	OMIM Accession: SCV003841241.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 34059824 Comment on evidence: In 2 unrelated patients (patients 4 and 5) and a father and his 4 children from another unrelated family (family 7) with juvenile amyotrophic lateral … (more) In 2 unrelated patients (patients 4 and 5) and a father and his 4 children from another unrelated family (family 7) with juvenile amyotrophic lateral sclerosis-27 (ALS27; 620285), Mohassel et al. (2021) identified heterozygosity for a 3-bp deletion (c.115_117delCTT, NM_006415.4) in exon 2 of the SPTLC1 gene, resulting in a deletion of Leu39 (L39del). The mutation was identified by whole-exome sequencing. In patients 4 and 5, the mutation occurred de novo. The variant was not present in the gnomAD database. (less)
Likely pathogenic (Jun 01, 2022)	no assertion criteria provided Method: provider interpretation	Neuropathy, hereditary sensory and autonomic, type 1A Affected status: yes Allele origin: inherited	Solve-RD Consortium Accession: SCV005200025.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 Comment: Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more) Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)	Comment: Variant confirmed as disease-causing by referring clinical team

Comment:

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34059824)

Comment:

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects SPTLC1 function (PMID: 34059824). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant has been observed in individual(s) with juvenile ALS (PMID: 34059824; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This variant, c.115_117del, results in the deletion of 1 amino acid(s) of the SPTLC1 protein (p.Leu39del), but otherwise preserves the integrity of the reading frame.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.	Mohassel P	Nature medicine	2021	PMID: 34059824

Text-mined citations for rs1197928094 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_006415.4(SPTLC1):c.112CTT[1] (p.Leu39del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1197928094 ...