ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4377G>T (p.Lys1459Asn) (rs201307101)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758029 SCV000577982 likely benign Cardiomyopathy 2016-12-15 reviewed by expert panel curation The filtering allele frequency of the c.4377G>T (p.Lys1459Asn) variant in the MYH7 gene is 0.0375% (34/66566) of European chromosomes by the Exome Aggregation Consortium (, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; PMID:29300372). Additionally, while computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3), this pathogenic evidence code (PP3) was not considered to be in conflict with a likely benign conclusion given the accuracy of computation prediction tools. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3; BS1
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000035906 SCV000059557 likely benign not specified 2018-05-11 criteria provided, single submitter clinical testing p.Lys1459Asn in exon 32 of MYH7: This variant is not expected to have clinical s ignificance because it has been identified in 0.05% (66/126506) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org/; dbSNP rs201307101). ACMG/AMP Criteria applied: PP3; BS1.
CSER_CC_NCGL; University of Washington Medical Center RCV000148704 SCV000190433 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000035906 SCV000208591 likely benign not specified 2018-01-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000162336 SCV000212636 uncertain significance Familial hypertrophic cardiomyopathy 1 2014-12-17 criteria provided, single submitter research This MYH7 Lys1459Asn variant was first reported by Van Driest SL, et al. (2004) as a novel variant in one HCM idex case. It has since been identified in other HCM patients (Laredo R, et al., 2007; García-Castro M, et al., 2009; Marsiglia JD, et al., 2013), and has also been identified in one sporadic case of Ebstein anomaly (Postma AV, et al., 2011). Segregation analysis by Laredo R, et al. (2007) identified 4 family members of the index case to be carriers of the MYH7 Lys1459Asn variant - 1 individual with mild disease; and 3 clinically unaffected family members (all >30 years old). We have identified this variant in 2 unrelated HCM cases, both of whom carry either a second pathogenic or likely pathogenic variant. Segregation analysis in one family did not show this MYH7 Lys1459Asn variant to segregate with disease (3 of 4 clinically affected individuals are not carriers). This variant is present (MAF=0.0003016) in the Exome Aggregation Consortium dataset ( Computational tools SIFT predicts this variant to be "deleterious", however, no prediction is called by PolyPhen-HCM. In summary, although this variant is present at a low frequency, weak or no evidence of the variant segregating with disease casts doubt on its role as the primary cause of HCM. We cannot rule out its potential as a modifying variant however, further evidence is required to fully understand its pathogenic role. Thus, we classify this variant as of "unknown significance".
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000177508 SCV000229389 uncertain significance not provided 2014-09-01 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000162336 SCV000256145 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000035906 SCV000264092 likely benign not specified 2015-05-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247619 SCV000319737 uncertain significance Cardiovascular phenotype 2017-12-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000466190 SCV000546179 uncertain significance Hypertrophic cardiomyopathy 2018-10-08 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1459 of the MYH7 protein (p.Lys1459Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs201307101, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 22765922, 24793961, 28356264), Ebstein anomaly (PMID: 21127202), and dilated cardiomyopathy (PMID: 23794396). ClinVar contains an entry for this variant (Variation ID: 43012). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000148704 SCV000740381 likely pathogenic Primary familial hypertrophic cardiomyopathy 2017-07-20 criteria provided, single submitter clinical testing
Color RCV000758029 SCV000913884 uncertain significance Cardiomyopathy 2018-07-06 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the LMM domain of the MYH7 protein, C-terminal tail region that forms the thick filament backbone and interacts with other proteins. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 22765922, 24793961, 28356264) and Ebstein anomaly (PMID: 21127202). This variant has also been identified in 79/276972 chromosomes (66/126506 non-Finnish European chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the relatively high frequency of this variant in the general population suggests that it is unlikely to be disease-causing, available evidence is insufficient to rule out the pathogenicity of this variant conclusively.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000177508 SCV000280349 likely pathogenic not provided 2012-09-06 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. Based on the strong case data, moderate segregation data, and sufficiently low frequency in general population samples, we consider this variant likely disease causing. In total this variant has been seen in 11 unrelated cases of MYH7-linked phenotypes (including one case in our center), with moderate segregation data in one family. In addition to patients with HCM, there is one patient with Ebstein’s and one patient with borderline hypertrophy with an abnormal papillary muscle anatomy and LVOT obstruction. We have seen this variant in one patient in our center, a Caucasian, non-Hispanic woman diagnosed with HCM at 71 years of age with a murmur first noted at 53 years of age. She underwent myectomy at 73 years of age. This variant was initially reported in one individual with HCM (van Driest et al 2004). That report included only sequencing of MYH7. However, a separate report by the same group reported on the incidence of multiple variants in this cohort after analysis of 9 sarcomere genes and based on that it appears this patient had only this one MYH7 variant (van Driest et al 2004). Ancestry data was not available. Laredo et al (2006) reported the variant in a family from their Spanish cohort, with some evidence of co-segregation; from 9 family members 2 had HCM and were genotype positive for the variant, 1 family member with HCM was not genotyped but was an obligate carrier (Laredo et al 2006). Three additional family members were found to be carriers, they had a normal phenotype (and were in their thirties). Garcia-Castro et al (2009) reported the variant in a single case of HCM from their Spanish cohort who underwent sequencing of 5 sarcomere genes. Given authors and recruitment site, this seems to overlap with a case later reported by Coto et al (2012) but not with the family reported by Laredo et al (2006). Postma et al (2010) reported one individual with this variant with Epstein’s anomaly but no hypertrophy from a cohort recruited in the Netherlands, the UK and Germany (of note, Ebstein's anomaly, often with noncompaction, has recently been associated with MYH7 variants (Budde et al 2007, Postma et al 2011, van Engelen et al 2011)). The Seidman group observed the variant in 1 of 1963 individuals from the Jackson Heart Study who underwent sequencing of eight sarcomere genes (Bick et al 2012). They note the following about that individual's phenotype: 52yo with LVWT 1.1 cm, LVDD 4.64 cm, LAD 4.24 cm, fractional shortening 0.37, 1 physical cardiovascular risk factor (not specified). Marsiglia et al (2014) observed the variant in 3 of 131 Brazilian patients with HCM who underwent sequencing of MYH7, MYBPC3, and TNNT2. Ackerman's group observed the variant in 2 patients in their cohort of 1053 unrelated patients with HCM who underwent DHLPC-based analysis of 9 sarcomere genes at Mayo (Bos et al 2014). Note that these cases likely overlap with prior reports by Ackerman's group (ex. van Driest et al 2004) and there is also a chance they overlap with internal cases from the clinical genetic testing labs. Ancestry data was not reported. Per their ClinVar submission (SCV000059557), LMM considers this variant to be of uncertain significance, based on the atypical presentation in the patient with Ebstein’s (perhaps this was before the MYH7-Ebstein’s link was reported), and the fact that most carriers in the Laredo et al family were mildly affected or unaffected. It also noted that LMM “detected this variant in 3 out of >2000 Caucasian probands, one of whom carried a second, pathogenic variant, and one only had borderline hypertrophy with an abnormal papillary muscle anatomy and LVOT obstruction (no diagnosis was available for the third proband).” It is notable that the majority of the cases with available ancestry data are from Spain and Brazil, presumably with overlapping ancestral roots. This could indicate a founder affect for a pathogenic variant or instead it may indicate that this is a common benign variant in these subgroups. However, given that Spanish and Portuguese people share substantial genetic ancestry with other Europeans (and at least a subset of Brazilian ancestry is European, primarily Portuguese), the European American data in NHLBI ESP is likely applicable. This is a semi conservative amino acid change with a polar, positive Lysine replaced with a polar, neutral Asparagine. A variant in a nearby codon (Ala1454Thr) has been reported to be associated with disease. Conservation analysis indicates that Lysine is highly conserved at codon 1459 down to C. elegans (Postma et al 2010). Polyphen2 predicts the variant to be probably damaging. Mutationtaster predicts it to be disease causing. I could find no other disease-associated variants at this codon (as of 8 Oct 2014 in ClinVar, dbSNP, Bos et al 2014 >1000 patient Mayo series). In total the variant has been seen in 1 of 7493 general population samples and published controls. The variant was not observed in 100 African American and 100 Caucasian control individuals by the Ackerman’s group (van Driest et al 2004, Bos et al 2014). Laredo et al did not observe the variant in 100 control individuals of unspecified ethnic background. Postma‘s group did not find the variant in 490 ethnically mixed controls. Garcia-Castro et al (2009) did not see the variant in 200 control individuals. In the 2008 report PGX did not disclose control data for this variant. The variant was reported online in 1 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of October 7, 2014). The phenotype of that individual 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 this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is listed in dbSNP with submissions related to the NHLBI ESP data and a submission from “Goldsteinlab” (rs201307101, as of October 7, 2014).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656145 SCV000678339 likely pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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