NM_014231.5(VAMP1):c.340del (p.Ile114fs) AND Spastic paraplegia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 27, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001855899.4

Allele description [Variation Report for NM_014231.5(VAMP1):c.340del (p.Ile114fs)]

NM_014231.5(VAMP1):c.340del (p.Ile114fs)

Genes:

TAPBPL:TAP binding protein like [Gene - OMIM - HGNC]
VAMP1:vesicle associated membrane protein 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_014231.5(VAMP1):c.340del (p.Ile114fs)

HGVS:

NC_000012.12:g.6464891del
NG_042188.2:g.11010del
NM_001297438.2:c.340del
NM_014231.5:c.340delMANE SELECT
NM_016830.4:c.340del
NM_199245.3:c.340del
NP_001284367.1:p.Arg114fs
NP_055046.1:p.Ile114fs
NP_058439.1:p.Arg114fs
NP_954740.1:p.Ser114fs
NC_000012.11:g.6574057del
NG_042188.1:g.11010del
NM_014231.3:c.340del
NM_014231.3:c.340delA
NM_014231.4:c.340del
NM_014231.5:c.340delAMANE SELECT
NR_123717.2:n.359del

Protein change:

I114fs

Links:

OMIM: 185880.0002; dbSNP: rs746220436

NCBI 1000 Genomes Browser:

rs746220436

Molecular consequence:

NM_001297438.2:c.340del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_014231.5:c.340del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_016830.4:c.340del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_199245.3:c.340del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_123717.2:n.359del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Spastic paraplegia
Identifiers:: MedGen: C0037772; Human Phenotype Ontology: HP:0001258

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002287785	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 27, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28168212, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002287785

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 27, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome.

Shen XM, Scola RH, Lorenzoni PJ, Kay CS, Werneck LC, Brengman J, Selcen D, Engel AG.

Ann Clin Transl Neurol. 2017 Feb;4(2):130-138. doi: 10.1002/acn3.387. Erratum in: Ann Clin Transl Neurol. 2017 May 08;4(5):356. doi: 10.1002/acn3.422.

PubMed [citation]

PMID:: 28168212
PMCID:: PMC5288468

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002287785.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this frameshift affects VAMP1 function (PMID: 28168212). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 619001). This frameshift has been observed in individuals with clinical features of autosomal recessive VAMP1-related conditions (PMID: 28168212; Invitae). This variant is present in population databases (rs746220436, gnomAD 0.006%). This sequence change results in a frameshift in the VAMP1 gene (p.Ile114Serfs*72). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the VAMP1 protein and extend the protein by 66 additional amino acid residues.

#	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 26, 2024

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