ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1090G>A (p.Ala364Thr) (rs794727046)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542022 SCV000623515 pathogenic Hypertrophic cardiomyopathy 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 364 of the MYBPC3 protein (p.Ala364Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant also falls at the last nucleotide of exon 12 of the MYBPC3 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 25740977, 21302287, 21239446, 20513729). ClinVar contains an entry for this variant (Variation ID: 454301). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001171149 SCV001333833 likely pathogenic Cardiomyopathy 2019-03-05 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786161 SCV000924849 likely pathogenic not provided 2017-04-25 no assertion criteria provided provider interpretation Testing for our patient was performed at Invitae. Given the moderate case data, possible effect on splicing, and absence in general population databases, we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 7 unrelated cases of HCM, one of which is a patient at our center. There is moderate case data. All of the cases are of Italian descent. Roncarati et al (2011) saw this variant in 1 patient with HCM and noted there may be a potential effect on splicing. Patient was recruited in Italy, but not in Padua. Calore et al. (2015) reports this variant in 5 index cases of HCM from a cohort in Padua, Italy. The variant has also been reported in other papers from overlapping groups in Italy (Fokstuen 2011; Melacini 2010), but these cases are not counted in the overall case count given possible redundancy of patients. The paper by Roncarati et al. also cites Smaniotto et al. (2009), but I was unable to find the actual paper. Even so, the authors were Italian and any cases reported in that paper could be overlapping. Per the lab report, algorithms predict that this variant could have an effect on splicing. Splicing and other protein-truncating variants in MYBPC3 are a frequent cause of HCM (Erdmann et al. 2001 & 2003; Stenson et al 2003; Harvard Sarcomere Protein Gene Mutation Database). Many MYBPC3 splice variants have been reported in association with HCM including IVS2-1G>A, IVS6-2A>C IVS7+1G>A, IVS8+1G>A, IVS12-2A>G, IVS14-2A>G, IVS16-1G>A, IVS22+1G>A, IVS24+1G>A, IVS28+1G>A, IVS32+1G>A, and IVS33+1G>A (Harvard Sarcomere Protein Gene Mutation Database). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy (Pan et al 2012). Another variant at the same codon Ala364Pro, which is considered a VUS by a reputable laboratory. That variant is absent from gnomAD. The variant is not listed 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, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD genomes is 51x and in gnomAD exomes is 32x.

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