Submissions for variant NM_007373.4(SHOC2):c.514C>T (p.Arg172Trp)

dbSNP: rs1057517872

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412927	SCV000490930	uncertain significance	not specified	2015-03-27	criteria provided, single submitter	clinical testing	The R172W variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R172W variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R172W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. One missense variant has been reported in the Human Gene Mutation Database in a nearby residue (M173I) in association with a rasopathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Fulgent Genetics, Fulgent Genetics	RCV002481272	SCV002785189	uncertain significance	Noonan syndrome-like disorder with loose anagen hair 1	2021-07-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524636	SCV003026691	uncertain significance	RASopathy	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 172 of the SHOC2 protein (p.Arg172Trp). This variant is not present in population databases (gnomAD no frequency). 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: 372586). 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.
Ambry Genetics	RCV004022163	SCV005026129	uncertain significance	Cardiovascular phenotype	2023-10-15	criteria provided, single submitter	clinical testing	The p.R172W variant (also known as c.514C>T), located in coding exon 1 of the SHOC2 gene, results from a C to T substitution at nucleotide position 514. The arginine at codon 172 is replaced by tryptophan, an amino acid with dissimilar 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.