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

gnomAD frequency: 0.00017  dbSNP: rs147204964

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041238	SCV000064929	likely benign	not specified	2012-07-26	criteria provided, single submitter	clinical testing	Val42Ile in exon 02 of SPRED1: The Val42Ile variant in SPRED1 was reported in on e individual with Legius syndrome (Spencer 2011). Furthermore, this variant was identified in one individual with clinical features within the Noonan spectrum b y our laboratory but was also found in an unaffected parent. However, this prob and also carried a BRAF variant that likely occurred de novo because it was not found in either parent of the proband. In addition, this variant has been identi fied in 0.07% (3/4400) of African American chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s147204964). Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or agai nst an impact to the protein. In summary, the Val42Ile variant is likely benign.
GeneDx	RCV000586558	SCV000209136	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in individuals with multiple cafe-au-lait macules, however, one individual also harbored a pathogenic variant in the NF2 gene and inheritance from an unaffected parent was seen in another individual; the authors felt V42I was benign (Hirata et al., 2016); Reported in individuals with multiple cafe-au-lait macules; authors do not classify the variant (Spencer et al., 2011); This variant is associated with the following publications: (PMID: 24469042, 24334617, 22753041, 31401120, 26635368, 21548021)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586558	SCV000699957	benign	not provided	2017-04-17	criteria provided, single submitter	clinical testing	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.
Invitae	RCV001086208	SCV000767050	likely benign	Legius syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813367	SCV002060690	benign	Noonan syndrome and Noonan-related syndrome	2020-09-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399395	SCV002669963	likely benign	Cardiovascular phenotype	2021-02-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.