NM_152594.3(SPRED1):c.124G>A (p.Val42Ile) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Benign(1);Uncertain significance(1) (Last evaluated: Apr 17, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000586558.4

Allele description [Variation Report for NM_152594.3(SPRED1):c.124G>A (p.Val42Ile)]

NM_152594.3(SPRED1):c.124G>A (p.Val42Ile)

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.124G>A (p.Val42Ile)
Other names:
p.V42I:GTC>ATC
HGVS:
  • NC_000015.10:g.38299464G>A
  • NG_008980.1:g.51614G>A
  • NM_152594.3:c.124G>AMANE SELECT
  • NP_689807.1:p.Val42Ile
  • NC_000015.9:g.38591665G>A
  • NM_152594.2:c.124G>A
  • c.124G>A
Protein change:
V42I
Links:
dbSNP: rs147204964
NCBI 1000 Genomes Browser:
rs147204964
Molecular consequence:
  • NM_152594.3:c.124G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000209136GeneDxcriteria provided, single submitter
Uncertain significance
(Aug 19, 2016)
germlineclinical testing

Citation Link,

SCV000699957Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Benign
(Apr 17, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Interaction between a Domain of the Negative Regulator of the Ras-ERK Pathway, SPRED1 Protein, and the GTPase-activating Protein-related Domain of Neurofibromin Is Implicated in Legius Syndrome and Neurofibromatosis Type 1.

Hirata Y, Brems H, Suzuki M, Kanamori M, Okada M, Morita R, Llano-Rivas I, Ose T, Messiaen L, Legius E, Yoshimura A.

J Biol Chem. 2016 Feb 12;291(7):3124-34. doi: 10.1074/jbc.M115.703710. Epub 2015 Dec 3.

PubMed [citation]
PMID:
26635368
PMCID:
PMC4751360

Review and update of SPRED1 mutations causing Legius syndrome.

Brems H, Pasmant E, Van Minkelen R, Wimmer K, Upadhyaya M, Legius E, Messiaen L.

Hum Mutat. 2012 Nov;33(11):1538-46. doi: 10.1002/humu.22152. Epub 2012 Aug 1. Review.

PubMed [citation]
PMID:
22753041
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000209136.11

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The V42I variant in the SPRED1 gene has not been reported previously as a disease-causing variant nor as a benign polymorphism, to our knowledge. This variant is a conservative substitution of one non-polar amino acid for another at a residue that is conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. The V42I variant was not observed at any significant frequency in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Projec. We interpret V42I as a variant of unknown significance. This variant has been observed to be maternally inherited.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699957.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: The SPRED1 c.124G>A (p.Val42Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the WH1/EVH1 domain and the PH domain-like (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC in 84/121220 control chromosomes from all ethnicities, but was predominantly observed in the South Asian subpopulation at a frequency of 0.003998 (66/16508 with 2 homozygotes). This frequency is about 1599 times the estimated maximal expected allele frequency of a pathogenic SPRED1 variant (0.0000025), which is very strong evidence that this is likely a benign polymorphism found primarily in the populations of South Asian origin. Multiple publications have identified the variant in patient populations, with one study showing lack of cosegregation due to an unaffected mother transmitting the allele to her affected daughter (Hirata_JBC_2016). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations (uncertain significance and likely benign); however, both reports in ClinVar used the ESP database during interpretation, where the variant had not been identified or identified at a very low frequency. The ExAC database, which is approximately 10 times larger than the ESP, shows a relatively high frequency of the variant, including homozygotes in the South Asian subpopulation, strongly supporting this variant as a benign polymorphism. LMM describes a Noonan-syndrome spectrum patient in their lab who was found to carry the variant, along with a de novo BRAF variant, and an unaffected parent also carried the variant of interest, further evidence for the benign nature of the variant. Taken together, this variant is classified as benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

Support Center