rs377225516
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000256.3(MYBPC3):c.184A>C(p.Thr62Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000234 in 1,601,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYBPC3 | ENST00000545968.6 | c.184A>C | p.Thr62Pro | missense_variant | Exon 2 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.184A>C | p.Thr62Pro | missense_variant | Exon 2 of 34 | 5 | ENSP00000382193.2 | |||
MYBPC3 | ENST00000544791.1 | n.184A>C | non_coding_transcript_exon_variant | Exon 2 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes AF: 0.000217 AC: 33AN: 152268Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000127 AC: 29AN: 228228Hom.: 0 AF XY: 0.000137 AC XY: 17AN XY: 123986
GnomAD4 exome AF: 0.000236 AC: 342AN: 1449466Hom.: 0 Cov.: 36 AF XY: 0.000232 AC XY: 167AN XY: 719936
GnomAD4 genome AF: 0.000217 AC: 33AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19AN XY: 74394
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:4
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See Variant Classification Assertion Criteria. -
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not specified Uncertain:3
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Thr62Pro (c.184A>C, T62P) in the MYBPC3 gene. Given the weak case data (reviewed below) we consider this a variant of uncertain significance. The variant has been seen in two cases of HCM (not including this patient's family). There is no segregation data available. Millat et al (2010) observed the variant in one HCM proband from their French cohort of 192 unrelated HCM patients. The patient did not have any other rare variants in MYBPC3, MYH7, TNNT2, or TNNI3. Sam Baxter at LMM shared that they have seen this variant once before in a patient with HCM and classify it as a variant of uncertain significance. In silico analysis with PolyPhen-2 predicts the variant to be benign. Per communication from Sam Baxter at LMM their sarcomere-specific PolyPhen also predicts it to be benign. They report that benign predictions by this tool are accurate 89% of the time. This is a non-conservative substitution, changing a polar threonine to a non-polar proline (Grantham score is 38). The threonine at codon 62 is not well conserved across species (GERP score of 0.4; mouse, rat and frog have a lysine; chicken and zebrafish have an asparagine). I could find no other variants at this codon associated with disease and only one nearby variant associated with HCM (p.Thr59Ala (Niimura et al 2002)). In total the variant has been seen in 3 of 6682 published controls and individuals from publicly available population datasets. The variant was reported online in 3 of 4289 Caucasian individuals and 0 of 2193 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of March 25th, 2014). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant was not observed in the following published control samples: 200 control individuals studied by Millat et al (2010). It is listed in dbSNP with submissions from NHLBI ESP and the LMM (rs377225516). -
Variant summary: MYBPC3 c.184A>C (p.Thr62Pro) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 484494 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYBPC3 causing Cardiomyopathy (0.00013 vs 0.001), allowing no conclusion about variant significance. c.184A>C has been reported in the literature in individuals affected with Cardiomyopathy (example: Millat_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23299917, 22958901, 24055113, 25637381, 37937776, 37652022, 20800588, 20624503, 38489124). ClinVar contains an entry for this variant (Variation ID: 42577). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Variant classified as Uncertain Significance - Favor Benign. The p.Thr62Pro vari ant in MYBPC3 has been reported in 1 individual with HCM (Millat 2010) and was i dentified by our laboratory in 1 Caucasian adult with HCM and 1 Caucasian indiv idual with teenage-onset DCM with LVH and conduction disease due to an alternate etiology. This variant has been identified in 34/116340 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSN P rs377225516). It was predicted to be benign using a computational tool clinica lly validated by our laboratory. This tool's benign prediction is estimated to b e correct 89% of the time (Jordan 2011). In summary, while the clinical signific ance of the p.Thr62Pro variant is uncertain, these data suggest that it is more likely to be benign. -
Hypertrophic cardiomyopathy Uncertain:2
This missense variant replaces threonine with proline at codon 62 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 32841044). This variant has been identified in 39/259624 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. -
This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 62 of the MYBPC3 protein (p.Thr62Pro). This variant is present in population databases (rs377225516, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with MYBPC3-related conditions (PMID: 20624503, 32841044, 37652022, 37937776). ClinVar contains an entry for this variant (Variation ID: 42577). 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 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. -
Cardiomyopathy Uncertain:1Benign:1
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This missense variant replaces threonine with proline at codon 62 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 32841044). This variant has been identified in 39/259624 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;C3715165:Left ventricular noncompaction 10 Uncertain:1
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Hypertrophic cardiomyopathy 4 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Cardiovascular phenotype Uncertain:1
The p.T62P variant (also known as c.184A>C), located in coding exon 2 of the MYBPC3 gene, results from an A to C substitution at nucleotide position 184. The threonine at codon 62 is replaced by proline, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Millat G et al. Eur J Med Genet., 2010 Jul;53:261-7; Alfares AA et al. Genet Med, 2015 Nov;17:880-8). This alteration has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Dorschner MO et al. Am. J. Hum. Genet., 2013 Oct;93:631-40; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is poorly 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. -
Left ventricular noncompaction 10 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at