Submissions for variant NM_000256.3(MYBPC3):c.1828G>A (p.Asp610Asn)

dbSNP: rs371564200

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035442	SCV000059090	uncertain significance	not specified	2010-09-10	criteria provided, single submitter	clinical testing	The Asp610Asn variant has not been reported in the literature, however it has be en identified by our laboratory in two individuals with clinical diagnoses of HC M, including one individual of Asian ethnicity who was homozygous for the Asp610 Asn variant and had childhood onset of disease. Aspartic acid (Asp) at position 610 is conserved across mammalian species, however it is not conserved in lower species. In summary, given the available data, the clinical significance of th is variant cannot be determined at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550478	SCV000623536	pathogenic	Hypertrophic cardiomyopathy	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 610 of the MYBPC3 protein (p.Asp610Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy. However, some individuals carried additional alleles in cardiomyopathy-related genes. (PMID: 20624503, 22857948, 27532257, 28214152, 28323875, 33782553; internal data). ClinVar contains an entry for this variant (Variation ID: 42575). 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. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 34097875). 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: 18533079, 20624503, 22361390, 25740977). 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.
Ambry Genetics	RCV000621171	SCV000739937	uncertain significance	Cardiovascular phenotype	2022-06-08	criteria provided, single submitter	clinical testing	The c.1828G>A (p.D610N) alteration is located in exon 19 (coding exon 19) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 1828, causing the aspartic acid (D) at amino acid position 610 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170950	SCV001333603	likely pathogenic	Cardiomyopathy	2023-06-09	criteria provided, single submitter	clinical testing
Loeys Lab, Universiteit Antwerpen	RCV000550478	SCV001572569	uncertain significance	Hypertrophic cardiomyopathy	2021-02-26	criteria provided, single submitter	clinical testing	This sequence change results in a missense variant in the MYBPC3 gene (p.(Asp610Asn)). Missense variants are significantly enriched in patients with HCM and are a known mechanism of disease (PP2) (PMID: 27532257). This variant is present in population databases (GnomAD 3/222558). This variant has been reported in the literature in several unrelated individuals with HCM (PMID:22857948; PMID:20624503; PMID:28214152; PMID:28323875). The variant affects a highly conserved nucleotide and a highly conserved amino acid. Prediction programs classify the variant as pathogenic (Align GVGD:C15; SIFT:pathogenic; MutationTaster: disease causing) (PP3). We identified this variant in a female HCM patient who carried an additional MYBPC3 variant (c.772G>A, classified as pathogenic, BP5). A second unrelated 14-year female patient with HCM presenting with OHCA and sudden cardiac death carried the variant in a homozygous state. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BP5, PP2,PP3).
Color Diagnostics, LLC DBA Color Health	RCV001170950	SCV001734320	uncertain significance	Cardiomyopathy	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant causes a large reduction in protein stability (PMID: 34097875). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 22857948, 27532257, 28214152, 2832387, 33241513, 33782553, 32841044, 35026164, 35581137, ClinVar SCV001572569.1, SCV000059090.5), including one individual who also carried another pathogenic variant in the MYBPC3 gene (PMID: 35581137). Two of the affected individuals were homozygous and had childhood onset of the disease (ClinVar SCV001572569.1, SCV000059090.5). This variant has been identified in 3/222558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002482956	SCV002787936	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2024-03-21	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137558	SCV003807351	uncertain significance	Hypertrophic cardiomyopathy 4	2022-12-19	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, PP3 supporting
All of Us Research Program, National Institutes of Health	RCV000550478	SCV004842434	uncertain significance	Hypertrophic cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 610 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant causes a large reduction in protein stability (PMID: 34097875). This variant has been reported in over ten individuals affected with hypertrophic cardiomyopathy (PMID: 22857948, 27532257, 28214152, 2832387, 33241513, 33782553, 32841044, 35026164, 35581137, ClinVar SCV001572569.1, SCV000059090.5), including one individual who also carried another pathogenic variant in the MYBPC3 gene (PMID: 35581137). Two of the affected individuals were homozygous and had childhood onset of the disease (ClinVar SCV001572569.1, SCV000059090.5). This variant has been identified in 3/222558 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003137558	SCV005400191	uncertain significance	Hypertrophic cardiomyopathy 4	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy 4 (HCM; MIM#115197). (I) 0108 - This gene is associated with both recessive and dominant disease. Dominant inheritance is frequently reported in adult-onset conditions and recessive inheritance results in a more severe early onset phenotype (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 32841044). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 6 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count in p.(Asp610His): 14 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 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. p.(Asp610His) has been reported as likely pathogenic but more frequently as a VUS, including in individuals with HCM (ClinVar, cardiodb). In addition, p.(Asp610Glu), p.(Asp610Val) and p.(Asp610Tyr) have been reported as VUS by multiple clinical testing laboratories (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported frequently as a VUS, and in more than 10 individuals with HCM (ClinVar, cardiodb, PMIDs: 32841044, 22857948). It has also been reported as homozygous or compound heterozygous in individuals with childhood onset HCM (PMID: 30009132, ClinVar). In addition, it has been reported as likely pathogenic by a clinical testing laboratory (ClinVar). (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
Blueprint Genetics	RCV000143912	SCV000188785	likely pathogenic	Primary dilated cardiomyopathy	2014-02-03	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148681	SCV000190405	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-06-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001729358	SCV001979612	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729358	SCV001980454	uncertain significance	not provided		no assertion criteria provided	clinical testing