ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2573G>A (p.Ser858Asn) (rs727503185)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620806 SCV000736137 uncertain significance Cardiovascular phenotype 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766355 SCV000208108 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing The S858N variant of uncertain significance in the MYBPC3 gene has previously been reported in association with HCM (Morita et al., 2008; Saltzman et al., 2010; Ho et al., 2013; Walsh et al., 2016). S858N was first reported in an individual with childhood-onset HCM and a family history of HCM and sudden cardiac death, who also harbored a common pathogenic variant in the MYBPC3 gene, phase unknown (Morita et al., 2008; Saltzman et al., 2010). Saltzman et al. (2010) proposed that the severe phenotype in this individual may be the result of an additive effect from both variants, however, it is unknown if S858N segregated with HCM in this family. This variant has also been observed, both independently and in conjunction with additional cardiogenetic variants, in multiple unrelated individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The S585N variant is not observed at significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, S858N is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000199338 SCV000254436 uncertain significance Hypertrophic cardiomyopathy 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 858 of the MYBPC3 protein (p.Ser858Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy including one individual with childhood onset disease in whom a pathogenic MYBPC3 allele was also identified (PMID: 20378854, 27532257). ClinVar contains an entry for this variant (Variation ID: 164070). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000199338 SCV000198843 likely pathogenic Hypertrophic cardiomyopathy 2010-12-17 criteria provided, single submitter clinical testing The Ser858Asn variant has been reported in one individual with childhood-onset H CM who carried a second, pathogenic variant in the MYBPC3 gene (Arg502Trp). The variant was not present among over 1200 control chromosomes (Morita 2008), suppo rting a pathogenic role. Our laboratory has reported this variant in isolation i n a total of two individuals with a clinical diagnosis of HCM. Serine (Ser) at p osition 858 is conserved across evolutionary distant species (mammals, birds, fr og, and fish), which also increases the likelihood that the change is pathogenic . In summary the variant?s presence in affected individuals, its absence from co ntrol chromosomes as well as evolutionary conservation of the affected amino aci d suggest that it is likely to be pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000151089 SCV000280240 uncertain significance not specified 2014-11-20 no assertion criteria provided clinical testing 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.Ser858Asn (c.2573G>A). in MYBPC3 Given the lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Per ClinVar, LMM also classifies it as a variant of uncertain significance (last reviewed by them in 2010, evidence and internal data not provided). The variant has been seen in at least one case of HCM (not including this patient's family), though that patient carried another pathogenic variant. Morita et al (2008) reported the presence of this variant in one individual with HCM. This patient was diagnosed early in childhood and also carried an additional variant in the MYBPC3 gene which is very likely disease causing and is actually the most common HCM-causing variant, present in 2.4% of patients with HCM (p.Arg502Trp). The authors did not report data on segregation or phasing. This is likely the same case that was reported by Saltzman et al (2010). Serine is highly conserved across species at position 858 in MYBPC3 gene. The amino acid change is chemically conservative, with a polar, neutral Serine being replaced by a polar, neutral Asparagine. Three is no variation at codon 858 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of August 27th, 2015). There is adequate coverage.This variant was not identified in 680 presumed healthy controls (Morita et al 2008).

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