Submissions for variant NM_000256.3(MYBPC3):c.104G>A (p.Arg35Gln)

gnomAD frequency: 0.00004  dbSNP: rs397515885

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035368	SCV000059016	uncertain significance	not specified	2013-04-26	criteria provided, single submitter	clinical testing	The Arg35Gln variant in MYBPC3 has been identified by our laboratory in 1 Caucas ian individual with HCM and was not identified in 416 Caucasian and 374 Black co ntrol chromosomes (LMM unpublished data). Data from large population studies is insufficient to further assess the frequency of this variant. The affected amino acid is not well conserved in evolution, suggesting that this change may be tol erated. Other computational analyses (biochemical amino acid properties, AlignGV GD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional information is needed to fully assess t he clinical significance of this variant.
GeneDx	RCV000766304	SCV000208120	uncertain significance	not provided	2022-08-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 27707468, 24111713, 33782553)
Invitae	RCV000459433	SCV000546413	uncertain significance	Hypertrophic cardiomyopathy	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 35 of the MYBPC3 protein (p.Arg35Gln). This variant is present in population databases (rs397515885, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 33782553). ClinVar contains an entry for this variant (Variation ID: 42503). 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.
Mendelics	RCV000988558	SCV001138324	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001190894	SCV001358529	uncertain significance	Cardiomyopathy	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 35 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 32841044, 32815737, 33495596). It has also been reported in an individual affected with sudden unexplained nocturnal death (PMID: 27707468) and in an individual affected with familial stroke (PMID: 36580209). This variant has been identified in 16/241052 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	RCV002504873	SCV002814068	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-07-30	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766304	SCV000925163	uncertain significance	not provided	2016-10-11	no assertion criteria provided	provider interpretation	p.Arg35Gln (c.104G>A) in exon 2 of the MYBPC3 gene (NM_000256.3) We have seen this variant in a person with HCM who had another very likely pathogenic variant. Testing was done through Invitae. Given the relatively high frequency in an ethnicity-matched population dataset and the presence of another likely pathogenic variant, we consider this variant of uncertain signficance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 3 unrelated cases of HCM (not including this patient's family). This is moderate case data. Berge et al., 2013 reported the variant in 2 HCM probands in Norway. LMM has seen it in a Caucasian person with HCM. The Invitae report notes that "The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine...algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0")." The variant was reported online in 7 of 44,255 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 10/11/2016). Specifically, the variant was observed in 6 of 3237 East Asian people (AF: 0.09%) and 1 of 24,933 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Please note that this site is covered in fewer than 80% of the individuals in Exac, and may represent a low quality site. A different variant at an adjacent base but the same codon, Arg35Trp, is also listed in ExAC, found in 5 of 22,239 people. Specifically, the variant was observed in 2 of 6436 South Asian people (AF: 0.015%) and 3 of 25,018 non-Finnish European people. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.