ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.124G>A (p.Val42Ile) (rs147204964)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 2016-08-19 criteria provided, single submitter clinical testing 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.
Integrated Genetics/Laboratory Corporation of America 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 2019-12-31 criteria provided, single submitter clinical testing

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