ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3624del (p.Lys1209fs) (rs397516029)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000231140 SCV000059253 pathogenic Hypertrophic cardiomyopathy 2020-03-23 criteria provided, single submitter clinical testing The p.Lys1209SerfsX28 variant in MYBPC3 (also reported as p.Pro1208fs in the literature) has been identified in at least 10 unrelated individuals with hypertrophic cardiomyopathy (HCM; including an individual who also carried a disease causing variant in another HCM associated gene) and segregated with disease in at least 2 affected relatives from 2 families (Li 2009, Zou 2013, Liu 2013, Liu 2015, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 42727) and has been identified in 0.005% (1/19456) of East Asian chromosomes and 1/127178 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1209 and leads to a premature termination codon 28 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PS4_Strong.
GeneDx RCV000158405 SCV000208340 pathogenic not provided 2018-07-06 criteria provided, single submitter clinical testing The c.3624delC mutation in the MYBPC3 gene has been reported previously in association with HCM (also referred to as Pro1208fs due to alternative nomenclature), and this mutation was absent from at least 280 control alleles (Li M et al., 2009; Zou Y et al., 2013). This mutation causes a shift in reading frame starting at codon Lysine 1209, changing it to a Serine, and creating a premature stop codon at position 28 of the new reading frame, denoted p.Lys1209SerfsX28. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift mutations in the MYBPC3 gene have been reported in association with HCM. In summary, c.3624delC in the MYBPC3 gene is interpreted as a disease-causing mutation.
Invitae RCV000231140 SCV000284244 pathogenic Hypertrophic cardiomyopathy 2019-05-03 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 32 of the MYBPC3 mRNA (c.3624delC), causing a frameshift at codon 1209. This creates a premature translational stop signal (p.Lys1209Serfs*28) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic. This particular variant has been reported in the literature (PMID: 20128375, 23711808, 23283745, 26090888). This variant is also known as p.Pro1208fs in the literature. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770322 SCV000901756 pathogenic Cardiomyopathy 2018-06-04 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158405 SCV000927618 pathogenic not provided 2018-04-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194064 SCV001363318 pathogenic Primary familial hypertrophic cardiomyopathy 2019-01-17 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.3624delC (p.Lys1209SerfsX28) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.3e-06 in 274834 control chromosomes (gnomAD). c.3624delC has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (Walsh_2017, Liu_2015, Murphy_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158405 SCV000924857 pathogenic not provided 2016-10-11 no assertion criteria provided provider interpretation p.Lys1209Serfs*28 (c.3624delC) in exon 32 of the MYBPC3 gene (NM_000256.3) We have seen this variant in 2 unrelated people with HCM. Testing was done by Invitae in both cases. Loss of function caused by frameshift variants are a well established mechanism of disease in this gene. In addition, there is strong case data for this variant and it is sufficiently rare in population datasets. Therefore, we consider this variant very likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Please note that this variant may also be called Pro1208ProfsX29. The variant has been seen in at least 10 unrelated cases of HCM (not including our patients' families). This is strong case data, but there is no reported segregation data. Li et al., 2009 reported this variant in a 59 year-old Chinese woman with HCM. Zou et al., 2013 reported this variant in 3 unrelated Chinese people with HCM. Liu et al., 2013 reported this variant in 2 unrelated Chinese people with HCM. Liu et al., 2015 reported the variant in 2 unrelated people with HCM. The variant is listed in ClinVar, classifed as Pathogenic by LMM, GeneDx, and Invitae (as of 10/11/2016). LMM reports that they have seen the variant in two families with HCM, one Asian and one Caucasian. Per the Invitae report, "This sequence change deletes 1 nucleotide from exon 32 of the MYBPC3 mRNA (c.3624delC), causing a frameshift at codon 1209. This creates a premature translational stop signal (p.Lys1209Serfs*28) and is expected to result in an absent or disrupted protein product." The variant was reported online in 2 of 140,093 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,216 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent (as of 10/2016). Specifically, the variant was observed in 1 of 9,432 individuals of East Asian descent (0.005% MAF) and 1 of 62,724 people of non-Finnish European descent. 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000231140 SCV001430859 pathogenic Hypertrophic cardiomyopathy 2019-12-10 no assertion criteria provided research The MYBPC Lys1209Serfs*28 has been reported previously in several HCM patients and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this MYBPC3 Lys1209Serfs*28 variant in two HCM probands, one of our probands has a family history of HCM, however genetic testing was not possible. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), has been reported in more than 6 unrelated HCM probands (PS4_moderate) and is rare in the general population (PM2), therefore we classify MYBPC3 Lys1209Serfs*28 as a "pathogenic" variant.

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