ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.676G>T (p.Val226Phe) (rs587780110)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561750 SCV000668286 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561750 SCV000682908 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515164 SCV000611441 uncertain significance Juvenile polyposis syndrome; Hereditary mixed polyposis syndrome 2 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000656784 SCV000149738 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.676G>T at the cDNA level, p.Val226Phe (V226F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Val226Phe was observed at an allele frequency of 0.06% (6/9848) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. BMPR1A Val226Phe occurs at a position that is conserved across species and is located in the intracellular and GS domains (UniProt, Howe 2004). Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Additionally, multiple splicing models predict this variant to damage the nearby natural splice acceptor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual splice effect of this variant is unknown. Based on currently available information, it is unclear whether BMPR1A Val226Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000123228 SCV000166534 uncertain significance Juvenile polyposis syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces valine with phenylalanine at codon 226 of the BMPR1A protein (p.Val226Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. It also falls at the first nucleotide of exon 9 of the BMPR1A coding sequence. This variant is present in population databases (rs587780110, ExAC 0.002%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 127902). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115829 SCV000600228 uncertain significance not specified 2017-03-29 criteria provided, single submitter clinical testing

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