Submissions for variant NM_005445.4(SMC3):c.3469G>C (p.Val1157Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586217	SCV005076667	uncertain significance	not specified	2024-04-23	criteria provided, single submitter	clinical testing	Variant summary: SMC3 c.3469G>C (p.Val1157Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251002 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.3469G>C in individuals affected with Cornelia De Lange Syndrome 3 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005101991	SCV005747272	uncertain significance	Cornelia de Lange syndrome 3	2024-03-15	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1157 of the SMC3 protein (p.Val1157Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMC3-related conditions. 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 SMC3 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.