ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1A>C (p.Met1Leu) (rs786203157)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492794 SCV000581498 pathogenic Hereditary cancer-predisposing syndrome 2019-10-31 criteria provided, single submitter clinical testing ​The p.M1L pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the BMPR1A gene and results from an A to C substitution at nucleotide position 1. This changes the amino acid from a methionine to a leucine at the initiation codon. This mutation has been described in a patient with sporadic juvenile polyposis (Calva-Cerqueira D. et al. Clin Genet. 2009 Jan;75(1):79-85). Functional studies for this variant are conflicting with aberrant subcellular localization, intact bone morphogenetic protein (BMP) signaling, and reduced BMPR1A protein expression being demonstrated; however, BMPR1A protein may have failed to be detected due to a loss of the N-terminal portion of the protein with use of an alternate downstream start codon (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000492794 SCV001351393 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-29 criteria provided, single submitter clinical testing This variant results in the loss of the translation start codon of the BMPR1A gene. The next in-frame methionine occurs at codon 29 that if used would delete the N-terminal signal peptide sequence (a.a. 1-23). The signal peptide motif is required for membrane-localization of the protein (PMID: 23433720). One study has shown that cells transfected with a construct containing this variant lacked the full-length BMPR1A protein product (PMID: 23433720). A protein product mislocalized to the cytoplasm was detected, but this study was inconclusive regarding the ability of the cytoplasmic protein to transduce BMP signaling. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) and has been reported in an individual affected with juvenile polyposis (PMID: 18823382). Different variants that also result in the loss of p.Met1 have reported as disease-causing in ClinVar (variation ID: 186704, 224521, 653050, 824482, 843741), suggesting that this codon is important for protein expression and/or function. Loss of BMPR1A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

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