ClinVar Miner

Submissions for variant NM_007373.3(SHOC2):c.610A>G (p.Ile204Val) (rs200015085)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229898 SCV000289856 uncertain significance Rasopathy 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 204 of the SHOC2 protein (p.Ile204Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs200015085, ExAC 0.02%). This variant has not been reported in the literature in individuals with SHOC2-related disease. ClinVar contains an entry for this variant (Variation ID: 240838). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 Clinical Services Laboratory,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.
Integrated Genetics/Laboratory Corporation of America 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

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