Submissions for variant NM_001202.6(BMP4):c.676C>T (p.Arg226Trp)

gnomAD frequency: 0.00025  dbSNP: rs140590144

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594335	SCV000702020	uncertain significance	not provided	2016-09-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112672	SCV001270357	uncertain significance	Orofacial cleft 11	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001112673	SCV001270358	likely benign	Microphthalmia with brain and digit anomalies	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000594335	SCV001985444	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a functional polymorphism in a patient with spina bifida aperta and his unaffected father and has been reported in a patient with colorectal cancer, but was also present in multiple healthy controls (Felder et al., 2002; Stenson et al., 2014; Lubbe et al., 2011); This variant is associated with the following publications: (PMID: 12404109, 20949628)
Invitae	RCV001854009	SCV002308371	uncertain significance	Microphthalmia with brain and digit anomalies; Orofacial cleft 11	2023-08-17	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with BMP4-related conditions. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 226 of the BMP4 protein (p.Arg226Trp). This variant is present in population databases (rs140590144, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 497489). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV003420028	SCV004114988	uncertain significance	BMP4-related disorder	2023-05-12	criteria provided, single submitter	clinical testing	The BMP4 c.676C>T variant is predicted to result in the amino acid substitution p.Arg226Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.057% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-54417301-G-A), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000594335	SCV004134137	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BMP4: BP4
Cytogenetics- Mohapatra Lab, Banaras Hindu University	RCV004555870	SCV005044987	pathogenic	See cases		no assertion criteria provided	case-control