Submissions for variant NM_000256.3(MYBPC3):c.3569G>A (p.Arg1190His)

gnomAD frequency: 0.00005  dbSNP: rs117354682

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766375	SCV000208395	uncertain significance	not provided	2020-03-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in one patient with left ventricular noncompaction cardiomyopathy in published literature, but familial segregation information and in vitro functional studies were not included (Miszalski-Jamka et al., 2017); This variant is associated with the following publications: (PMID: 22763267, 28798025)
Ambry Genetics	RCV000252750	SCV000318642	uncertain significance	Cardiovascular phenotype	2023-03-01	criteria provided, single submitter	clinical testing	The p.R1190H variant (also known as c.3569G>A), located in coding exon 32 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3569. The arginine at codon 1190 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in cases with left ventricular non-compaction cardiomyopathy; however, clinical details were limited (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10; Mazzarotto F et al. Genet Med. 2021 May;23(5):856-864). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000527109	SCV000623598	uncertain significance	Hypertrophic cardiomyopathy	2024-08-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1190 of the MYBPC3 protein (p.Arg1190His). This variant is present in population databases (rs117354682, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 42722). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV001190896	SCV001358531	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1190 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has been identified in 13/280282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002490481	SCV002780988	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-10-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000766375	SCV003817149	uncertain significance	not provided	2021-12-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000527109	SCV004836587	uncertain significance	Hypertrophic cardiomyopathy	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1190 of the MYBPC3 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 37466024) and in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has been identified in 13/280282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035597	SCV000059248	uncertain significance	not specified	2008-05-23	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766375	SCV000925159	uncertain significance	not provided	2017-08-15	no assertion criteria provided	provider interpretation	MYBPC3, Exon 32, c.3569G>A (p.Arg1190His), heterozygous, Uncertain Significance Given the high frequency in gnomAD we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per the lab report this variant has not been reported in association with disease. However, there are multiple assertions in ClinVar, all as variant of uncertain significance (GeneDx, CHEO, LMM, Ambry). None of these entries provide case data. Per the lab report "Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT,, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have notconfirmed by published functional studies and their clinical significance is uncertain." The variant was reported online in 13 of 138479 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in multiple ancestral groups with the highest frequency in African individuals (MAF=0.02084%). The phenotype of those individuals is not publicly available.