ClinVar Genomic variation as it relates to human health

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.

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 4e-06 in 246920 control chromosomes (gnomAD). c.3624delC has been reported in the literature in multiple individuals affected with Hypertrophic Cardiomyopathy (example, Liu_2015, and Murphy_2016, Ross_2017, Walsh_2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20128375, 23283745, 28498465, 28614222, 26914223, 26090888, 27532257, 28241245, 28790153, 28408708, 28615295, 27112610, 23711808, 23549607, 29497013, 33673806)

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42727). This variant is also known as p.Pro1208fs. This premature translational stop signal has been observed in individual(s) with MYBPC3-related conditions (PMID: 20128375, 23283745, 23711808, 26090888). This variant is present in population databases (rs397516030, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Lys1209Serfs*28) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Heterozygous variants are frequently reported in adult onset conditions, however recessive inheritance results in a more severe early onset phenotype (OMIM). (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 32 of 35). (P) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic in patients with HCM (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in multiple individuals with HCM, and it considered to be a common pathogenic variant in the Chinese population (ClinVar, HGMD, PMID: 31941943). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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).

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.