NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter) AND Legius syndrome

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 17, 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:: RCV000001883.14

Allele description [Variation Report for NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)]

NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

15q14

Genomic location:

Preferred name:

NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)

HGVS:

NC_000015.10:g.38299410C>T
NG_008980.1:g.51560C>T
NM_152594.3:c.70C>TMANE SELECT
NP_689807.1:p.Arg24Ter
NC_000015.9:g.38591611C>T
NM_152594.2:c.70C>T

Protein change:

R24*; ARG24TER

Links:

OMIM: 609291.0002; dbSNP: rs121434313

NCBI 1000 Genomes Browser:

rs121434313

Molecular consequence:

NM_152594.3:c.70C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000022039	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2007)	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000291524	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 8, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 19920235, 21089071, 17704776, 28492532
SCV004013733	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17704776, 25741868
SCV004020392	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005087183	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17704776, 28378438, 31370276, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Legius syndrome in fourteen families.

Denayer E, Chmara M, Brems H, Kievit AM, van Bever Y, Van den Ouweland AM, Van Minkelen R, de Goede-Bolder A, Oostenbrink R, Lakeman P, Beert E, Ishizaki T, Mori T, Keymolen K, Van den Ende J, Mangold E, Peltonen S, Brice G, Rankin J, Van Spaendonck-Zwarts KY, Yoshimura A, Legius E.

Hum Mutat. 2011 Jan;32(1):E1985-98. doi: 10.1002/humu.21404.

PubMed [citation]

PMID:: 21089071
PMCID:: PMC3038325

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000022039.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 70C-T transition in exon 3 of the SPRED1 gene, resulting in an arg24-to-ter (R24X) substitution. The R24X mutation was present in normal skin and melanocytes from a cafe-au-lait spot of 1 patient, but melanocytes from the cafe-au-lait spot showed an additional somatic SPRED1 mutation. The 2 mutations were located on different alleles, suggesting that SPRED1 function was completely absent in these cells.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000291524.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1810). This premature translational stop signal has been observed in individuals with Legius syndrome (PMID: 17704776, 19920235, 21089071). This variant is present in population databases (rs121434313, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg24*) in the SPRED1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPRED1 are known to be pathogenic (PMID: 17704776).

#	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 3billion, SCV004013733.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000001810 / PMID: 17704776). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020392.1

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

Description

Variant summary: SPRED1 c.70C>T (p.Arg24X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251158 control chromosomes (gnomAD). c.70C>T has been reported in the literature in multiple individuals affected with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) and has been found to segregate with the disease phenotype in at least one family (e.g. Brems_2007). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 17704776). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005087183.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

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 located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other 5' NMD-escape 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. This variant has been reported as pathogenic, and observed in several individuals with a neurofibromatosis-like phenotype, cafe-au-lait or Legius syndrome (ClinVar, PMID: 28378438, PMID: 17704776, PMID: 31370276). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (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: Oct 20, 2024

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