Submissions for variant NM_001202.6(BMP4):c.733C>T (p.Arg245Trp)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002283384	SCV002571902	uncertain significance	not specified	2022-08-09	criteria provided, single submitter	clinical testing	Variant summary: BMP4 c.733C>T (p.Arg245Trp) results in a non-conservative amino acid change located in the TGF-beta, propeptide domain (IPR001111) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.733C>T in individuals affected with Microphthalmia With Brain And Digit Anomalies and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV003146533	SCV003831484	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing
Invitae	RCV003774932	SCV004567878	uncertain significance	Microphthalmia with brain and digit anomalies; Orofacial cleft 11	2023-01-25	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BMP4 protein function. ClinVar contains an entry for this variant (Variation ID: 1705059). This variant has not been reported in the literature in individuals affected with BMP4-related conditions. This variant is present in population databases (rs769454152, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 245 of the BMP4 protein (p.Arg245Trp).