ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.505A>T (p.Ile169Phe) (rs878854668)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226965 SCV000288393 uncertain significance Juvenile polyposis syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with phenylalanine at codon 169 of the BMPR1A protein (p.Ile169Phe). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 239862). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000236060 SCV000294015 uncertain significance not provided 2017-03-23 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.505A>T at the cDNA level, p.Ile169Phe (I169F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Ile169Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Ile169Phe occurs at a position that is conserved in mammals and is located in the transmembrane domain (Howe 2004). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may strengthen a cryptic splice acceptor site downstream of the natural acceptor site and possibly lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BMPR1A Ile169Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565550 SCV000668301 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)

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