Submissions for variant NM_007373.4(SHOC2):c.973-5del

dbSNP: rs730881016

Total submissions: 7

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, part of Exact Sciences	RCV000248887	SCV000311812	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000259557	SCV000360443	benign	Noonan syndrome-like disorder with loose anagen hair 1	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813415	SCV002060627	benign	Noonan syndrome and Noonan-related syndrome	2021-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000159104	SCV002398101	benign	RASopathy	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381520	SCV002693402	benign	Cardiovascular phenotype	2021-01-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.