Submissions for variant NM_000256.3(MYBPC3):c.994G>A (p.Glu332Lys)

gnomAD frequency: 0.00003  dbSNP: rs397516086

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035691	SCV000059342	uncertain significance	not specified	2019-08-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Glu332Lys variant in MYBPC3 has been reported in 2 individuals with DCM and 1 individual with HCM, one of whom carried an additional pathogenic variant in MYBPC3 (Walsh 2017, LMM data). It did not segregate with disease in 1 affected family member with DCM (LMM data). It has also been identified in 0.02% (7/34248) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #42815). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: PP3, BS1_Supporting, BS4.
GeneDx	RCV000766319	SCV000208259	uncertain significance	not provided	2016-10-07	criteria provided, single submitter	clinical testing	The E332K variant in the MYBPC3 gene has been reported as a variant of uncertain significance in association with DCM (Pugh et al., 2014). Pugh et al. (2014) identified the E332K variant in two unrelated individuals with a clinical and family history of DCM, one of whom also harbored a likely pathogenic variant in the MYH7 gene. The E332K variant has been also reported as a pathogenic variant, but clinical information was not provided (Zimmerman R et al., 2010). The E332K variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E332K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae	RCV000628961	SCV000749871	uncertain significance	Hypertrophic cardiomyopathy	2023-08-27	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 42815). This missense change has been observed in individuals with hypertrophic cardiomyopathy and dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs397516086, gnomAD 0.02%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 332 of the MYBPC3 protein (p.Glu332Lys).
Mendelics	RCV000988548	SCV001138311	uncertain significance	Hypertrophic cardiomyopathy 4	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001188895	SCV001356068	uncertain significance	Cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 332 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257). It has also been reported in individuals affected with dilated cardiomyopathy; one of these individuals also carried a pathogenic variant in the MYH7 gene (PMID: 24503780, 27532257). This variant has been identified in 8/246592 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.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000766319	SCV000925167	uncertain significance	not provided	2017-12-21	no assertion criteria provided	provider interpretation	We identified this variant in a patient with DCM. Testing was performed at Invitae. SCICD Classification: variant of uncertain significance based on relatively high frequency in the general population, weak case data (and different phenotypes), and variant type. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Case data (not including our patient): 1 DCM, 1 HCM Pugh et al 2014 - redundant with LMM Clinvar data. Zimmerman 2010 - technical paper on sequencing chip; redundant with LMM ClinVar data. Walsh et al 2016 - reports an additional patient with this variant with HCM tested at Oxford laboratory. Classified as VUS. The supplement also includes the previously reported two LMM DCM cases. Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "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." Conservation data: Glu is highly conserved. Nearby pathogenic variants at this codon or neighboring codons: There are other nearby pathogenic variants, but they are nonsense variants, not missense. Population data: Highest MAF in Latino population: 0.02096%. The variant was reported online in 8 of 121912 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 7 of 16700 individuals of Latino descent (MAF=0.02%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.