ClinVar Miner

Submissions for variant NM_007373.3(SHOC2):c.973-5del (rs730881016)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159104 SCV000209047 benign Rasopathy 2014-09-23 criteria provided, single submitter clinical testing The variant is found in NOONAN panel(s).
PreventionGenetics,PreventionGenetics RCV000248887 SCV000311812 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000259557 SCV000360443 benign Noonan syndrome-like disorder with loose anagen hair 1 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000248887 SCV001361946 benign not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: SHOC2 c.973-5delT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.011 in 249088 control chromosomes, predominantly at a frequency of 0.089 within the South Asian subpopulation in the gnomAD database, including 156 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3560-folds over the estimated maximal expected allele frequency for a pathogenic variant in SHOC2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.973-5delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

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