ClinVar Miner

Submissions for variant NM_005448.2(BMP15):c.202C>T (p.Arg68Trp) (rs104894763)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519346 SCV000616655 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing The R68W variant in the BMP15 gene has been published in association with familial premature ovarian failure (POF) with secondary amenorrhea (Di Pasquale et al., 2006). The R68W was reported in a 16 year old female who had a familial form of POF, her mother, grandmother, and six maternal cousins going through menopause before 28years old, however, no segregation studies were performed to document that R68W was present in all of the affected individuals (Di Pasquale et al., 2006). The R68W localizes in the proregion, which is essential for the processing and secretion of bioactive dimers and functional studies demonstrated that R68W lead to marked reductions of mature protein production (Rossetti et al., 2009). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports that R68W was observed in 12/6724 alleles (0.18%) from individuals of European background. The R68W variant is a non-conservative amino acid substitution of a nonpolar amino acid for a basic amino acid, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position that is not conserved across species, in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R61Q, R76C, R76H) have been reported in the Human Gene Mutation Database in association with POF (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R68W as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000357909 SCV000482601 likely benign Ovarian Dysgenesis 2016-06-14 criteria provided, single submitter clinical testing
OMIM RCV000012229 SCV000032463 pathogenic Premature ovarian failure 4 2009-05-01 no assertion criteria provided literature only

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