NM_000256.3:c.2210C>T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4
The NM_000256.3(MYBPC3):c.2210C>T(p.Thr737Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,854 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | c.2210C>T | p.Thr737Met | missense_variant | Exon 23 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | c.2210C>T | p.Thr737Met | missense_variant | Exon 22 of 34 | 5 | ENSP00000382193.2 | |||
| MYBPC3 | ENST00000544791.1 | n.2210C>T | non_coding_transcript_exon_variant | Exon 23 of 27 | 5 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248960Hom.: 0 AF XY: 0.0000666 AC XY: 9AN XY: 135128
GnomAD4 exome AF: 0.000176 AC: 257AN: 1461658Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121AN XY: 727120
GnomAD4 genome 0.000158 AC: 24AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12AN XY: 74334
ClinVar
Submissions by phenotype
not provided Uncertain:4
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The MYBPC3 c.2210C>T; p.Thr737Met variant (rs199893357, ClinVar Variation ID: 42608) is reported in the literature in individuals affected with dilated and/or hypertrophic cardiomyopathy (Bick 2012, Burstein 2021, Harper 2021, Helms 2020, Mazzarotto 2020, McGurk 2023, Rippert 2023, Walsh 2017). This variant is found in the general population with an overall allele frequency of 0.008% (21/280,356 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.297). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bick AG et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet. 2012 Sep 7;91(3):513-9. PMID: 22958901. Burstein DS et al. Genetic variant burden and adverse outcomes in pediatric cardiomyopathy. Pediatr Res. 2021 May;89(6):1470-1476. PMID: 32746448. Harper AR et al. Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet. 2021 Feb;53(2):135-142. PMID: 33495597. Helms AS et al Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med. 2020 Oct;13(5):396-405. PMID: 32841044. Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. PMID: 31983221. McGurk KA et al. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet. 2023 Sep 7;110(9):1482-1495. PMID: 37652022. Rippert AL et al. Evaluating the Utility of a New Pathogenicity Predictor for Pediatric Cardiomyopathy. Human Mutation, 2023 Oct; https://doi.org/10.1155/2023/8892833. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. PMID: 27532257. -
BP4 -
Identified in patients with cardiomyopathy in published literature (PMID: 22958901, 31983221, 27532257, 33782553, 23861362, Rippert et al., 2023, 37652022, 32841044, 33495597); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22958901, 23861362, 21310275, 31983221, 32746448, 33782553, 27532257, 32841044, Rippert2023[article], 37652022, 33495597) -
not specified Uncertain:2
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.Thr737Met in MYBPC3 The p.Thr737Met variant is novel. The c.2210C>T substitution was identified in exon 23 of MYBPC3, resulting in a non-conservative amino acid substitution of a polar neutral threonine with non-polar neutral methionine. The threonine residue is conserved across other mammalian species. In silico analysis with PolyPhen2 predicts the variant to be probably damaging. A variant has been reported in association with HCM at a nearby codon (p.Arg733Cys, Van Driest et al 2004). In total the variant has not been seen in ~4 of ~7,134 laboratory controls and individuals from publicly available population datasets. The variant was recently reported online in 2 of 4197 Caucasian individuals and 0 of 2077 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of April 9th, 2012). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Of note, other variants with strong evidence for pathogenicity have been seen in this dataset at a similar frequency, so this does not necessarily mean that the variant is not pathogenic. The variant is also listed in dbSNP (rs199893357) with note that it was observed in 2 of ~560 individuals in the NHGRI ClinSeq cohort. 1000 genomes lists the variant, but only in reference to the dbSNP entry. The p.Thr737Met variant was not detected in up to 300 individuals of Caucasian and African American ancestry tested at GeneDx. The pathogenicity of this novel variant is currently uncertain. It may contribute to the patient’s cardiomyopathy or it may be a rare benign variant. -
The Thr737Met variant in MYBPC3 has not been reported in the literature though i t has been identified in 1 individual with HCM out of >1900 Caucasian probands ( 3800 chromosomes) tested by our laboratory. This low frequency is consistent wit h a pathogenic role. However, threonine (Thr) at position 737 is not completely conserved in evolution, suggesting that a change may be tolerated. Furthermore, this variant was predicted to be benign using a novel computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well -established clinical significance. This tool's benign interpretation is estimat ed to be correct 89% of the time, which suggests but does not prove that this va riant is benign (Jordan 2011). In summary, the clinical significance of this var iant cannot be determined without additional studies. -
Cardiomyopathy Uncertain:2
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This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 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 Uncertain:2
This missense variant replaces threonine with methionine at codon 737 of the MYBPC3 protein. Computational prediction suggests that this variant may have a neutral impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33495597). This variant has also been reported in two individuals affected with dilated cardiomyopathy (PMID: 31983221 and 32746448). This variant has also been identified in 21/280356 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 methionine, which is neutral and non-polar, at codon 737 of the MYBPC3 protein (p.Thr737Met). This variant is present in population databases (rs199893357, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of MYBPC3-related conditions (PMID: 27532257, 31983221, 32746448, 33782553; internal data). ClinVar contains an entry for this variant (Variation ID: 42608). 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. -
Hypertrophic cardiomyopathy 4 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Cardiovascular phenotype Uncertain:1
The c.2210C>T (p.T737M) alteration is located in exon 23 (coding exon 23) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2210, causing the threonine (T) at amino acid position 737 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Left ventricular noncompaction 10 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at