Submissions for variant NM_007373.4(SHOC2):c.610A>G (p.Ile204Val)

gnomAD frequency: 0.00006  dbSNP: rs200015085

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229898	SCV000289856	uncertain significance	RASopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 204 of the SHOC2 protein (p.Ile204Val). This variant is present in population databases (rs200015085, gnomAD 0.01%). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 28074886). ClinVar contains an entry for this variant (Variation ID: 240838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHOC2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV000314432	SCV000360438	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.
GeneDx	RCV000479328	SCV000574438	uncertain significance	not provided	2017-04-03	criteria provided, single submitter	clinical testing	The I204V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 2/10232 (0.02%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). I204V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174950	SCV001338411	likely benign	not specified	2020-02-07	criteria provided, single submitter	clinical testing	Variant summary: SHOC2 c.610A>G (p.Ile204Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250862 control chromosomes (gnomAD). The observed variant frequency is approximately 2.7 fold 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 benign. c.610A>G has been reported in the literature in an individual affected with SIDS (Naubauer_2017). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, three classified the variant as VUS while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000479328	SCV000925217	uncertain significance	not provided	2016-03-02	no assertion criteria provided	provider interpretation