ClinVar Genomic variation as it relates to human health

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.

ACMG classification criteria: PM2 moderated, PP3 supporting

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).

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; Invitae). 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.

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.

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.

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.