Submissions for variant NM_001032283.3(TMPO):c.529A>G (p.Ser177Gly)

gnomAD frequency: 0.00003  dbSNP: rs765922156

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522550	SCV000617918	uncertain significance	not provided	2015-12-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TMPO gene. The c.529 A>G (S177G) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This 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. c.529 A>G occurs at a nucleotide position that is conserved across species. The c.529 A>G variant results in the S177G 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. Alternatively, in silico splice prediction programs predict c.529 A>G may result in the creation of a cryptic splice donor site and cause abnormal gene splicing. However, in the absence of functional mRNA studies, the physiological consequences of this variant cannot be precisely determined. Furthermore, only two missense variants in the TMPO gene have been reported in the Human Gene Mutation Database (Stenson et al., 2014), and the physiological impact of TMPO haploinsuffiency is unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792924	SCV000932253	uncertain significance	Loeys-Dietz syndrome 2	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 177 of the TMPO protein (p.Ser177Gly). This variant is present in population databases (rs765922156, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TMPO-related conditions. ClinVar contains an entry for this variant (Variation ID: 449608). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.