Submissions for variant NM_001202.6(BMP4):c.224A>G (p.Lys75Arg)

gnomAD frequency: 0.00001  dbSNP: rs777501416

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000289710	SCV000387024	uncertain significance	Orofacial cleft 11	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000344659	SCV000387025	uncertain significance	Cleft Lip +/- Cleft Palate, Autosomal Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000400269	SCV000387026	uncertain significance	Syndromic Microphthalmia, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000438985	SCV000529332	uncertain significance	not provided	2016-06-23	criteria provided, single submitter	clinical testing	The K75R variant in the BMP4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The K75R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The K75R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret K75R as a variant of uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002480133	SCV002778146	uncertain significance	Microphthalmia with brain and digit anomalies; Orofacial cleft 11	2022-02-02	criteria provided, single submitter	clinical testing
Invitae	RCV002480133	SCV003286207	uncertain significance	Microphthalmia with brain and digit anomalies; Orofacial cleft 11	2023-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 75 of the BMP4 protein (p.Lys75Arg). This variant is present in population databases (rs777501416, gnomAD 0.02%). 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: 313353). This variant has not been reported in the literature in individuals affected with BMP4-related conditions.