NM_000256.3:c.1828G>C
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM5PP3_ModeratePP5
The NM_000256.3(MYBPC3):c.1828G>C(p.Asp610His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,598,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D610N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Publications
- hypertrophic cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- hypertrophic cardiomyopathy 4Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- left ventricular noncompaction 10Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- atrial fibrillationInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | NM_000256.3 | MANE Select | c.1828G>C | p.Asp610His | missense | Exon 19 of 35 | NP_000247.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| MYBPC3 | ENST00000545968.6 | TSL:5 MANE Select | c.1828G>C | p.Asp610His | missense | Exon 19 of 35 | ENSP00000442795.1 | ||
| MYBPC3 | ENST00000399249.6 | TSL:5 | c.1828G>C | p.Asp610His | missense | Exon 18 of 34 | ENSP00000382193.2 | ||
| MYBPC3 | ENST00000544791.1 | TSL:5 | n.1828G>C | non_coding_transcript_exon | Exon 19 of 27 | ENSP00000444259.1 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152146Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000315 AC: 7AN: 222558 AF XY: 0.0000249 show subpopulations
GnomAD4 exome AF: 0.0000664 AC: 96AN: 1446838Hom.: 0 Cov.: 35 AF XY: 0.0000640 AC XY: 46AN XY: 718236 show subpopulations
Age Distribution
GnomAD4 genome 0.0000460 AC: 7AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74310 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Left ventricular noncompaction 10 Pathogenic:1Uncertain:2
ClinGen MYBPC3: PP3
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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
not provided Pathogenic:1Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20624503, 20800588, 22361390, 27532257, 28074886, 28538763, 22958901, 27618852, 28356264, 21835320, 29032884, 32746448, 33782553, 35838873, 37652022, 33495597, 29710196, 18533079, 25740977, 36788754, 31983221, 35130036, 32531501, 40710799, 40225148, 40879562, 39633578, 34714385)
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
This missense variant replaces aspartic acid with histidine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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: 18533079, 20624503, 28356264, 28538763, 32531501, 33782553, 33495597). One of these individuals was compound heterozygous with a known pathogenic mutation in the same gene (PMID: 28538763). While this individual was reported to show severe phenotype, all other carriers of either of the two variants showed no clinical signs of hypertrophic cardiomyopathy. This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221) and in two individuals affected with sudden infant death syndrome (PMID: 22361390, 28074886). This variant has been identified in 8/253926 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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 610 of the MYBPC3 protein (p.Asp610His). This variant is present in population databases (rs371564200, gnomAD 0.008%). This missense change has been observed in individuals with hypertrophic cardiomyopathy, sudden infant death syndrome, and/or ventricular fibrillation (PMID: 8533079, 20624503, 22361390, 25740977, 28074886, 28356264, 29032884). ClinVar contains an entry for this variant (Variation ID: 42576). 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. This variant disrupts the p.Asp610 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22857948, 33782553, 34097875; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular phenotype Pathogenic:1Uncertain:1
The p.D610H variant (also known as c.1828G>C), located in coding exon 19 of the MYBPC3 gene, results from a G to C substitution at nucleotide position 1828. The aspartic acid at codon 610 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in multiple individuals with hypertrophic cardiomyopathy (HCM), but several of the probands were also heterozygous for pathogenic variants in other HCM-associated genes (Millat G et al. Eur J Med Genet 2010 Sep-Oct;53:261-7; Olivotto I et al. J. Am. Coll. Cardiol., 2011 Aug;58:839-48; Calore C et al. J. Med. Genet., 2015 May;52:338-47; Galati G et al. Circ Heart Fail, 2016 Sep;9; Rafael JF et al. Arq. Bras. Cardiol., 2017 Apr;108:354-360; Maurizi N et al. JAMA Cardiol, 2018 Jun;3:520-525). This alteration was also reported in cases of sudden infant death syndrome; however, limited clinical information was provided (Brion M et al. Forensic Sci. Int., 2012 Jun;219:278-81; Neubauer J et al. Eur. J. Hum. Genet., 2017 04;25:404-409). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PS4_mod, PM2, PM5_supp, PP3
Cardiomyopathy Uncertain:2
This missense variant replaces aspartic acid with histidine at codon 610 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 20624503, 28356264, 28538763, 32531501, 33782553, 33495597, 38489124). Two of these individuals also carried different pathogenic variants in the same gene (PMID: 28538763, 38489124). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 31983221), in one individual affected with an unspecified cardiomyopathy (PMID: 37477868), and in two infants affected with sudden death (PMID: 22361390, 28074886). This variant has been identified in 8/253926 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:2
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy (DCM) (MIM#615396), hypertrophic cardiomyopathy (HCM) (MIM#115197) and left ventricular noncompaction (MIM#615396). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a dominant condition (8 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Both p.(Asp610Val) and p.(Asp610Asn) have previously been classified as VUS by diagnostic laboratories in ClinVar, with the latter being reported in HCM patients (ClinVar, PMIDs: 28323875, 22857948). (I) 0808 - Previous evidence of pathogenicity for this variant is conflicting. This variant has been reported in HCM patients, some of whom also harbour another variant either in MYBPC3 or other cardiac genes. In addition, it has been identified patients with idiopathic ventricular fibrillation and sudden infant death syndrome. Overall, it has been classified as both likely pathogenic and predominantly as a VUS by diagnostic laboratories in ClinVar (ClinVar, PMIDs: 28538763, 32531501, 20624503, 21750094, 29032884, 22361390, 21835320). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
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.
not specified Uncertain:1
The p.Asp610His variant in MYBPC3 has been detected in 8 individuals with HCM (O livotto 2008, Millat 2010, Brito 2012, Rafael 2017 and LMM unpublished data) and one child who died from sudden infant death syndrome (SIDS; Brion 2012). Two of these individuals carried additional pathogenic variants and one individual was homozygous for the p.Asp610His variant (Rafael 2017, LMM data). In one family, this variant segregated with disease in 2 affected relatives, but was not presen t in an additional affected relative, raising the possibility that it may not be disease causing. The variant has also been identified in multiple older individ uals without disease. This variant has also been reported in ClinVar (Variation ID: 42576). This variant has also been identified in 6/113666 European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs371564200). Computational prediction tools suggest that the p.Asp610His variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Asp 610His variant is uncertain. ACMG/AMP Criteria applied: PP3; PS4_Supporting; BP2 .
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at