Submissions for variant NM_001032283.3(TMPO):c.565+2368G>A

gnomAD frequency: 0.00058  dbSNP: rs138295270

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037749	SCV000061411	uncertain significance	not specified	2013-07-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Arg650His varia nt in TMPO has now been identified by our laboratory in 1 Caucasian infant with LVNC and 1 Black infant with DCM (LMM unpublished data). This variant has also b een identified in 0.1% (5/4406) of African American chromosomes by the NHLBI Exo me Sequencing Project and 0.6% (3/490) of Black chromosomes by the 1000 Genomes project (http://evs.gs.washington.edu/EVS/; dbSNP rs138295270). Computational an alyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, a nd SIFT) do not provide strong support for or against an impact to the protein. While this frequency suggests that this variant is more likely benign, it is too low to confidently rule out a disease-causing role. Additional information is n eeded to fully assess its clinical significance.
GeneDx	RCV001703885	SCV000236462	likely benign	not provided	2020-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002310999	SCV000319870	uncertain significance	Inborn genetic diseases	2015-07-15	criteria provided, single submitter	clinical testing	The p.R650H variant (also known as c.1949G>A), located in coding exon 4 of the TMPO gene, results from a G to A substitution at nucleotide position 1949. The arginine at codon 650 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs138295270. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.14% (3/2098) total alleles studied. The highest observed frequency was 1.22% (2/164) Luhya alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.04% (5/13006) total alleles studied, having been observed in 0.11% (5/4406) African American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852787	SCV002257556	uncertain significance	Loeys-Dietz syndrome 2	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 650 of the TMPO protein (p.Arg650His). This variant is present in population databases (rs138295270, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 44669). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMPO protein function. 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.
Revvity Omics, Revvity	RCV001703885	SCV004238065	uncertain significance	not provided	2020-09-23	criteria provided, single submitter	clinical testing