ClinVar Miner

Submissions for variant NM_152594.3(SPRED1):c.26A>T (p.Asp9Val) (rs200157475)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041240 SCV000064931 benign not specified 2018-05-25 criteria provided, single submitter clinical testing p.Asp9Val in exon 1 of SPRED1: This variant is classified as benign because it h as been identified in 0.5% (49/9150) of Ashkenazi Jewish chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs20015 7475). ACMG/AMP criteria applied: BA1.
GeneDx RCV000680360 SCV000530149 likely benign not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001082112 SCV000645821 benign Legius syndrome 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000680360 SCV001149385 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000041240 SCV001338222 benign not specified 2020-02-24 criteria provided, single submitter clinical testing Variant summary: SPRED1 c.26A>T (p.Asp9Val) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 195612 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been internally reported (PTPN11 c.172A>T, p.Asn58Tyr), providing supporting evidence for a benign role. Four ClinVar submitters (evaluation after 2014) cites the variant as uncertain significance (1x), likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as benign.

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