NM_152594.3(SPRED1):c.867dup (p.Ser290fs) AND Legius syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003314118.3

Allele description [Variation Report for NM_152594.3(SPRED1):c.867dup (p.Ser290fs)]

NM_152594.3(SPRED1):c.867dup (p.Ser290fs)

Gene:

SPRED1:sprouty related EVH1 domain containing 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

15q14

Genomic location:

Preferred name:

NM_152594.3(SPRED1):c.867dup (p.Ser290fs)

HGVS:

NC_000015.10:g.38351196dup
NG_008980.1:g.103346dup
NM_152594.3:c.867dupMANE SELECT
NP_689807.1:p.Ser290fs
NC_000015.9:g.38643391_38643392insA
NC_000015.9:g.38643397dup

Protein change:

S290fs

Molecular consequence:

NM_152594.3:c.867dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Legius syndrome
Synonyms:: Neurofibromatosis type 1 like syndrome
Identifiers:: MONDO: MONDO:0012669; MedGen: C1969623; Orphanet: 137605; OMIM: 611431

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004013236	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004651516	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19920235, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004013236

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004651516

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 3, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.

Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, et al.

JAMA. 2009 Nov 18;302(19):2111-8. doi: 10.1001/jama.2009.1663. Erratum in: JAMA. 2010 Jun 23;303(24):2477.

PubMed [citation]

PMID:: 19920235

See all PubMed Citations (3)

Details of each submission

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004013236.1

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

Description

PVS1, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004651516.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SPRED1 protein in which other variant(s) (p.Cys418Alafs*6) have been determined to be pathogenic (PMID: 19920235; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with SPRED1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ser290Ilefs*10) in the SPRED1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 155 amino acid(s) of the SPRED1 protein.

#	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: Sep 29, 2024

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