ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.118G>A (p.Asp40Asn) (rs587781556)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129572 SCV000184354 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000464702 SCV000552868 uncertain significance Juvenile polyposis syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 40 of the BMPR1A protein (p.Asp40Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587781556, ExAC 0.001%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 141179). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000521982 SCV000618476 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.118G>A at the cDNA level, p.Asp40Asn (D40N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Asp40Asn was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. BMPR1A Asp40Asn occurs at a position that is not conserved and is located in the MH1 domain (Howe 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Asp40Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129572 SCV000903244 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing

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