11-47346636-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000256.3(MYBPC3):c.917G>A(p.Arg306Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,534,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R306W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.917G>A | p.Arg306Gln | missense_variant | 11/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.917G>A | p.Arg306Gln | missense_variant | 11/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.917G>A | p.Arg306Gln | missense_variant | 10/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.917G>A | p.Arg306Gln | missense_variant, NMD_transcript_variant | 11/27 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000139 AC: 2AN: 144302Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000307 AC: 7AN: 228156Hom.: 0 AF XY: 0.0000242 AC XY: 3AN XY: 124086
GnomAD4 exome AF: 0.0000173 AC: 24AN: 1390304Hom.: 0 Cov.: 45 AF XY: 0.0000145 AC XY: 10AN XY: 688710
GnomAD4 genome AF: 0.0000139 AC: 2AN: 144302Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 69894
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 11, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Arg306Gln varia nt in MYBPC3 has now been identified by our laboratory in one individual with DC M and one individual with HCM. It has also been identified in 1/4036 African Am erican chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washingt on.edu). Arginine (Arg) at position 306 is not evolutionarily conserved and the change to glutamine (Gln) was predicted to be benign using a computational tool clinically validated by our laboratory. This tool's benign prediction is estimat ed to be correct 89% of the time (Jordan 2011). Although these data support that the Arg306Gln variant is more likely benign, additional information is needed t o fully assess the clinical significance of this variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2023 | Identified in a patient with cardiomyopathy in published literature (Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 31983221) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 306 of the MYBPC3 protein (p.Arg306Gln). This variant is present in population databases (rs373204728, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42802). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2021 | The c.917G>A (p.R306Q) alteration is located in exon 11 (coding exon 11) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 917, causing the arginine (R) at amino acid position 306 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at