rs201307101
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. BS1PP3
This summary comes from the ClinGen Evidence Repository: 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 (http://exac.broadinstitute.org), 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA014901/MONDO:0004994/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MYH7 | NM_000257.4 | c.4377G>T | p.Lys1459Asn | missense_variant | Exon 32 of 40 | ENST00000355349.4 | NP_000248.2 | |
| MYH7 | NM_001407004.1 | c.4377G>T | p.Lys1459Asn | missense_variant | Exon 31 of 39 | NP_001393933.1 | ||
| MHRT | NR_126491.1 | n.735C>A | non_coding_transcript_exon_variant | Exon 5 of 6 |
Ensembl
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000299 AC: 75AN: 251252Hom.: 0 AF XY: 0.000331 AC XY: 45AN XY: 135806
GnomAD4 exome AF: 0.000482 AC: 704AN: 1461804Hom.: 0 Cov.: 34 AF XY: 0.000433 AC XY: 315AN XY: 727206
GnomAD4 genome 0.000230 AC: 35AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25467552, 21127202, 19150014, 15358028, 22958901, 17125710, 24793961, 26654849, 22765922, 25342278, 23299917, 28381408, 25637381, 24093860, 23074333, 23794396, 27247418, 29181379, 15757018, 29300372, 30871747, 31006259, 31737537, 30847666, 33297573, 34542152, 31847883, 32894683, 24714796, 28356264, 37466024, 37937776, 37652022, 28912206) -
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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 -
Hypertrophic cardiomyopathy 1 Pathogenic:1Uncertain:2Benign:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Benign. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Hypertrophic cardiomyopathy is known to be an incompletely penetrant disease, although data specific to this gene is lacking (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to asparagine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of MYH7-related disease. (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail domain (Pfam). (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. Although this variant has conflicting interpretations in ClinVar, it has been reviewed as likely benign by the ClinGen expert panel (ClinGen). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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 (http://exac.broadinstitute.org/). 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". -
Cardiomyopathy Uncertain:2Benign:2
This missense variant replaces lysine with asparagine at codon 1459 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 22765922, 24793961, 28356264), in an individual affected with Ebstein anomaly (PMID: 21127202), and in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has also been identified in 83/282640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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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 (http://exac.broadinstitute.org), 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 -
This missense variant replaces lysine with asparagine at codon 1459 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 22765922, 24793961, 28356264), in an individual affected with Ebstein anomaly (PMID: 21127202), and in an individual affected with dilated cardiomyopathy (PMID: 30871747). This variant has also been identified in 83/282640 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not specified Uncertain:1Benign:2
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. -
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Variant summary: MYH7 c.4377G>T (p.Lys1459Asn) results in a non-conservative amino acid change located in the myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251252 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MYH7 causing Cardiomyopathy (0.0003 vs 0.0013), allowing no conclusion about variant significance. c.4377G>T has been reported in the literature in multiple individuals affected with cardiomyopathy, including those affected with hypertrophic cardiomyopathy (e.g., VanDriest_2004, Laredo_2006, Gomez_2017, vanLint_2019), dilated cardiomyopathy (e.g., Sousa_2019), long QT syndrome (e.g., Quenin_2017), and an individual with an Ebstein anomaly (Postma_2011). However, these reports do not show strong evidence for causality (e.g., lack of co-segregation data) and therefore do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28356264, 29300372, 17125710, 21127202, 28912206, 30871747, 15358028, 31006259, 30847666). Multiple ClinVar submitters (evaluation after 2014), including the ClinGen Cardiomyopathy Variant Curation Expert Panel, have cited the variant with conflicting assessments (likely benign (including the expert panel), n = 8; VUS, n = 6; benign, n = 1; likely pathogenic, n = 2). The ClinGen Cardiomyopathy Variant Curation Expert Panel states that this variant occurs at a high enough frequency to be classified as likely benign based on their defined thresholds (Kelly_2018). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Primary familial hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
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Hypertrophic cardiomyopathy Uncertain:1Benign:1
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This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1459 of the MYH7 protein (p.Lys1459Asn). This variant is present in population databases (rs201307101, gnomAD 0.05%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 17125710, 19150014, 21127202, 22765922, 23794396, 24793961, 28356264, 30871747, 33297573, 37466024, 37937776). ClinVar contains an entry for this variant (Variation ID: 43012). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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. -
Wolff-Parkinson-White pattern Pathogenic:1
This variant was identified in an individual with Wolff-Parkinson-White syndrome -
Myosin storage myopathy Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Congenital myopathy with fiber type disproportion Uncertain:1
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BP6. -
MYH7-related skeletal myopathy Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at