ClinVar Miner

Submissions for variant NM_007373.4(SHOC2):c.961A>G (p.Thr321Ala)

gnomAD frequency: 0.00002  dbSNP: rs779218281
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193225 SCV001361945 uncertain significance not specified 2019-09-09 criteria provided, single submitter clinical testing Variant summary: SHOC2 c.961A>G (p.Thr321Ala) results in a non-conservative amino acid change located in the Leucine-rich repeat domain (IPR001611) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250668 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.961A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001859169 SCV002141649 uncertain significance RASopathy 2024-11-19 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 321 of the SHOC2 protein (p.Thr321Ala). This variant is present in population databases (rs779218281, gnomAD 0.007%). 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: 928787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx RCV002280165 SCV002568558 likely benign not provided 2022-08-26 criteria provided, single submitter clinical testing See Variant Classification Assertion Criteria.
Ambry Genetics RCV002379748 SCV002695720 uncertain significance Cardiovascular phenotype 2025-01-20 criteria provided, single submitter clinical testing The c.961A>G (p.T321A) alteration is located in exon 4 (coding exon 3) of the SHOC2 gene. This alteration results from a A to G substitution at nucleotide position 961, causing the threonine (T) at amino acid position 321 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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