rs397515885
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM5BP4_Moderate
The NM_000256.3(MYBPC3):c.104G>A(p.Arg35Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000658 in 1,609,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R35W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.104G>A | p.Arg35Gln | missense_variant | 2/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.104G>A | p.Arg35Gln | missense_variant | 2/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.104G>A | p.Arg35Gln | missense_variant | 2/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.104G>A | p.Arg35Gln | missense_variant, NMD_transcript_variant | 2/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000525 AC: 8AN: 152262Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000664 AC: 16AN: 241052Hom.: 0 AF XY: 0.0000760 AC XY: 10AN XY: 131504
GnomAD4 exome AF: 0.0000672 AC: 98AN: 1457444Hom.: 0 Cov.: 35 AF XY: 0.0000635 AC XY: 46AN XY: 724866
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152380Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74526
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Arg35Gln variant in MYBPC3 has been reported in 4 individuals with hypertrophic cardiomyopathy, and at least 1 individual with HCM who was double heterozygous for a different likely pathogenic variant in MYBPC3 (Berge 2014 PMID: 24111713, Thompson 2021 PMID: 33782553, LMM data). It has also been identified in 0.07% (12/17642) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 42503). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP2. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2024 | 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, 35653365) - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 11, 2016 | 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. - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 05, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 30, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 05, 2023 | 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. - |
Hypertrophic cardiomyopathy 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 29, 2019 | The c.104G>A (p.R35Q) alteration is located in exon 2 (coding exon 2) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 104, causing the arginine (R) at amino acid position 35 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