Submissions for variant NM_007373.4(SHOC2):c.841+12G>A

gnomAD frequency: 0.00019  dbSNP: rs201258692

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128040	SCV000171631	benign	not specified	2012-08-10	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.
PreventionGenetics, part of Exact Sciences	RCV000128040	SCV000311811	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000356842	SCV000360442	benign	Noonan syndrome-like disorder with loose anagen hair 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128040	SCV001361944	benign	not specified	2019-09-09	criteria provided, single submitter	clinical testing	Variant summary: SHOC2 c.841+12G>A 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 251252 control chromosomes, predominantly at a frequency of 0.088 within the South Asian subpopulation in the gnomAD database, including 155 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3520-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.841+12G>A 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002055801	SCV002394131	benign	RASopathy	2024-01-28	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000128040	SCV001922253	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723705	SCV001954875	likely benign	not provided		no assertion criteria provided	clinical testing