ClinVar Miner

Submissions for variant NM_007373.4(SHOC2):c.1477C>T (p.Leu493Phe)

gnomAD frequency: 0.00009  dbSNP: rs1026930115
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001331722 SCV001523822 uncertain significance Noonan syndrome 3 2019-07-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV001558056 SCV001779927 likely benign not provided 2019-10-10 criteria provided, single submitter clinical testing
Invitae RCV001871822 SCV002119268 uncertain significance RASopathy 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 493 of the SHOC2 protein (p.Leu493Phe). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SHOC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1030213). 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 expected to disrupt SHOC2 protein function with a positive 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.
Ambry Genetics RCV002395732 SCV002699474 uncertain significance Cardiovascular phenotype 2021-12-03 criteria provided, single submitter clinical testing The p.L493F variant (also known as c.1477C>T), located in coding exon 7 of the SHOC2 gene, results from a C to T substitution at nucleotide position 1477. The leucine at codon 493 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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