NM_152594.3(SPRED1):c.796_797del (p.Met266fs) AND Legius syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 21, 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:: RCV000204318.12

Allele description [Variation Report for NM_152594.3(SPRED1):c.796_797del (p.Met266fs)]

NM_152594.3(SPRED1):c.796_797del (p.Met266fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

15q14

Genomic location:

Preferred name:

NM_152594.3(SPRED1):c.796_797del (p.Met266fs)

HGVS:

NC_000015.10:g.38351125_38351126del
NG_008980.1:g.103275_103276del
NM_152594.3:c.796_797delMANE SELECT
NP_689807.1:p.Met266fs
NC_000015.9:g.38643326_38643327del
NM_152594.2:c.796_797del
NM_152594.2:c.796_797delAT

Protein change:

M266fs

Links:

dbSNP: rs864622410

NCBI 1000 Genomes Browser:

rs864622410

Molecular consequence:

NM_152594.3:c.796_797del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000260510	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17704776, 22751498, 28492532
SCV000782325	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002581091	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086142	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17704776, 25074460, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1.

Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernández H, Burlingame AL, McCormick F.

Genes Dev. 2012 Jul 1;26(13):1421-6. doi: 10.1101/gad.190876.112.

PubMed [citation]

PMID:: 22751498
PMCID:: PMC3403010

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260510.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met266Valfs*4) in the SPRED1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 179 amino acid(s) of the SPRED1 protein. This premature translational stop signal has been observed in individuals with cafe au lait macules (PMID: 17704776; Invitae). ClinVar contains an entry for this variant (Variation ID: 220172). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SPRED1 function (PMID: 17704776, 22751498). For these reasons, this variant has been classified as Pathogenic.

#	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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782325.1

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

#	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 MGZ Medical Genetics Center, SCV002581091.1

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

#	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		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086142.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Legius syndrome (MIM#611431). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other downstream protein-truncating variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least two affected individuals with cafe-au-lait spots with or without learning disabilities (PMIDs: 17704776, 25074460) and classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

Last Updated: Sep 29, 2024

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