Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000766840 | SCV000250806 | uncertain significance | not provided | 2014-07-21 | criteria provided, single submitter | clinical testing | p.Leu22Pro (CTA>CCA): c.65 T>C in exon 2 of the SMAD9 gene (NM_001127217.2). A variant of unknown significance has been identified in the SMAD9 gene. To our knowledge, the L22P variant has not been published as a mutation nor as a benign polymorphism. The L22P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, the NHLBI Exome Sequencing Project and the 1000 Genomes Project identified L22P in 0.1%-0.6% of alleles from individuals of European background (of note, L22P was detected in 3/168 or 1.8% of alleles in Utah Residents with Northern and Western European ancestry), indicating it may be a rare benign variant in this population. Additionally, missense mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in PAH-ARRHYTHMIA |
| Laboratory for Molecular Medicine, |
RCV000199749 | SCV000711358 | uncertain significance | not specified | 2017-03-06 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The p.Leu22Pro vari ant in SMAD9 has not been previously reported in individuals with pulmonary hype rtension, but has been identified in 0.2% (152/66658) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s111748421). This variant has also been identified in ClinVar (Variant ID: 21381 1). Computational prediction tools and conservation analysis suggest that the p. Leu22Pro variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, while the clinical significanc e of the p.Leu22Pro variant is uncertain, its frequency suggests that it is more likely to be benign. |
| ARUP Laboratories, |
RCV001284818 | SCV001470857 | uncertain significance | Pulmonary hypertension, primary, 2 | 2023-11-29 | criteria provided, single submitter | clinical testing | The SMAD9 c.65T>C; p.Leu22Pro variant (rs111748421) is reported in the literature in individuals affected with unexplained high bone mass (Gregson 2019). This variant is reported in ClinVar (Variation ID: 213811), and is found in the general population with an overall allele frequency of 0.14% (387/282856 alleles, including 4 homozygotes) in the Genome Aggregation Database. The leucine at codon 22 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.878). Due to limited information, the clinical significance of the p.Leu22Pro variant is uncertain at this time. References: Gregson CL et al. A rare SMAD9 mutation identifies the BMP signaling pathway as a potential osteoanabolic target. J Bone Miner Res. 2020 Jan;35(1):92-105. PMID: 31525280 |
| Labcorp Genetics |
RCV001284818 | SCV003480318 | benign | Pulmonary hypertension, primary, 2 | 2024-01-18 | criteria provided, single submitter | clinical testing | |
| Laboratory of Diagnostic Genome Analysis, |
RCV000766840 | SCV001798947 | uncertain significance | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000766840 | SCV001967947 | uncertain significance | not provided | no assertion criteria provided | clinical testing |