Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000036381 | SCV000060036 | uncertain significance | not specified | 2017-07-21 | criteria provided, single submitter | clinical testing | The p.Asn47Lys variant in MYL2 has been reported in 3 individuals with HCM (Ande rsen 2001, Hougs 2005, Alvarez-Acosta 2014) and has also been reported in ClinVa r (Variation ID 31766). This variant has also been identified by our laboratory in three Caucasian individuals (2 with HCM, and 1 with LVNC, hypotonia and motor delay), one of whom (with HCM) carried a second, likely pathogenic variant in a nother gene. In addition, the p.Asn47Lys variant has been identified in 48/12666 0 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad .broadinstitute.org; dbSNP rs199474808). Studies suggest that this variant may a lter contraction function of cardiac cells (Szczesna-Cordary 2004, Abraham 2009, Greenberg 2009, Greenberg 2010). However, these in vitro assays may not accurat ely represent biological function. This variant was predicted to be pathogenic u sing a computational tool clinically validated by our laboratory. This tool's pa thogenic prediction is estimated to be correct 94% of the time (Jordan 2011). H owever, asparagine (Asn) at position 47 is not conserved in mammals and addition al computational prediction tools suggest that the p.Asn47Lys variant may not im pact the protein, though this information is not predictive enough to rule out p athogenicity. In summary, due to the conflicting information currently available , additional data is needed to fully assess the clinical significance of the p.A sn47Lys variant. |
CSER _CC_NCGL, |
RCV000148715 | SCV000190445 | 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 |
Gene |
RCV000024457 | SCV000208855 | uncertain significance | not provided | 2022-12-20 | criteria provided, single submitter | clinical testing | Reported in patients with HCM in published literature (Andersen et al., 2001; Hougs et al., 2005; Berge et al., 2014; Stava et al., 2022); several patients harbored an additional cardiogenetic variant; Identified in a Caucasian infant with a history of apneic episodes who died at three months of age due to sudden infant death syndrome (SIDS) (Methner et al., 2016); Reported in three individuals without HCM from the offspring cohort in the Framingham Heart Study (Bick et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 27435932, 31104103, 23299917, 15483641, 14594949, 20855589, 24111713, 28301460, 28467684, 16837010, 19150977, 26116789, 26284228, 28518168, 30706179, 18929571, 35653365, 11748309, 22958901) |
Ambry Genetics | RCV000254541 | SCV000317938 | uncertain significance | Cardiovascular phenotype | 2023-01-30 | criteria provided, single submitter | clinical testing | The p.N47K variant (also known as c.141C>A), located in coding exon 3 of the MYL2 gene, results from a C to A substitution at nucleotide position 141. The asparagine at codon 47 is replaced by lysine, an amino acid with similar properties. This alteration has been observed in a number of individuals with a personal and/or family history that is consistent with MYL2-related disease, some of whom also carried alterations in other cardio-related genes (Andersen PS et al. J Med Genet, 2001 Dec;38:E43; Hougs L et al. Eur J Hum Genet, 2005 Feb;13:161-5; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Lopes LR et al. Heart, 2015 Feb;101:294-301; Maron BA et al. Nat Commun, 2021 02;12:873; Ambry internal data). Functional studies indicate that this alteration may have some impact on protein function; however, the clinical significance of the observed functional impacts is unclear (Szczesna-Cordary D et al. J. Biol. Chem., 2004 Jan;279:3535-42; Abraham TP et al. Cardiovasc. Res., 2009 Apr;82:84-92; Greenberg MJ et al. J. Mol. Cell. Cardiol., 2009 Jan;46:108-15; Karabina A et al. Arch. Biochem. Biophys., 2015 Aug;580:14-21). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV000528536 | SCV000638387 | uncertain significance | Hypertrophic cardiomyopathy 10 | 2022-09-23 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 47 of the MYL2 protein (p.Asn47Lys). This variant is present in population databases (rs199474808, gnomAD 0.04%). This missense change has been observed in individual(s) with MYL2-related conditions (PMID: 11748309, 24111713, 27435932). ClinVar contains an entry for this variant (Variation ID: 31766). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects MYL2 function (PMID: 14594949, 18929571, 19150977, 20855589). 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. |
Agnes Ginges Centre for Molecular Cardiology, |
RCV000584767 | SCV000692507 | uncertain significance | Hypertrophic cardiomyopathy 1 | 2017-03-03 | criteria provided, single submitter | research | This MYL2 Asn47Lys variant has been identified in one published HCM proband with marked progression of hypertrophy over two years, and was absent from 150 controls (Anderson PS, et al., 2001). The proband was later found to be a carrier of second variant; MYH7 Arg1712Trp (Hougs L, et al., 2005). This variant has an allele frequency of 0.01% (22 alleles) in the Exome Aggregation Consortium population dataset (http://exac.broadinstitute.org/) which is more frequent than we would expect for an HCM causative variant. We have identified this variant in a HCM proband, who progressed to heart failure and consequently received a heart transplant. Computational tools SIFT and PolyPhen-2 predict the variant to be "tolerated" and "benign" respectively, however MutationTaster and PolyPhen-HCM predict this variant to be "disease-causing" and "pathogenic". Functional studies suggest this variant may impact contraction (Szczesna-Cordary D, et al., 2004)and force, particularly under loaded conditions (Abraham TP, et al., 2009; Greenberg MJ, et al., 2009; Greenberg MJ, et al., 2010). The variant was discussed at our multidisciplinary pathogenicity meeting and it was agreed based on current literature, and the greater than expected frequency in the ExAC dataset, that it should be considered a variant of "uncertain significance", though noted this may be downgraded in future. |
CHEO Genetics Diagnostic Laboratory, |
RCV000769367 | SCV000900755 | uncertain significance | Cardiomyopathy | 2022-08-30 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000769367 | SCV000903432 | uncertain significance | Cardiomyopathy | 2023-04-18 | criteria provided, single submitter | clinical testing | This missense variant replaces asparagine with lysine at codon 47 of the MYL2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies in vitro and in transgenic animal models have shown that this variant causes a reduction in Ca2+ binding, an increase in Ca2+ sensitivity of myofibrillar ATPase activity, and in a reduction in force and power output (PMID: 14594949, 18929571, 19150977, 20855589, 31315475, 33558530). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11748309, 24111713, 25351510, 33558530) and in an individual affected with unexplained sudden death (PMID: 27435932). This variant also occurs at an appreciable frequency in the general population and has been identified in 55/282836 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant has also been found in individuals referred for cardiomyopathy genetic testing at a commercial laboratory, several of whom harbored other deleterious variants (ClinVar variation ID 31766). In summary, although experimental studies indicate this variant may have a deleterious impact on protein function, this variant has not been observed in a significant number of affected individuals and has not been shown to segregate with disease in family studies. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Illumina Laboratory Services, |
RCV000528536 | SCV001266578 | uncertain significance | Hypertrophic cardiomyopathy 10 | 2017-04-27 | criteria provided, single submitter | clinical testing | 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. |
Victorian Clinical Genetics Services, |
RCV000528536 | SCV002767987 | uncertain significance | Hypertrophic cardiomyopathy 10 | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 55 heterozygotes, 0 homozygotes). (SP) 0308 - Population frequency for this variant is out of keeping with known incidence of hypertrophic cardiomyopathy. (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated calcium-binding site (PDB; PMID: 14594949). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been identified in HCM patients, both of whom also harboured another variant in a different gene. It was also reported in a case of sudden infant death syndrome and three offspring from the Framingham Heart Study, although their clinical status was not indicated. Within the VCGS cohort, it was reported in three HCM patients, one of whom had another VUS in DSP and the other two harbouring pathogenic variants in MYBPC3. Finally, this variant has been classified as a VUS by diagnostic laboratories in ClinVar (VCSG; ClinVar; PMID: 24111713, 11748309, 15483641, 27435932, 22958901). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies demonstrated impaired myosin kinetics and animal models recapitulated HCM phenotype (PMID: 28467684, 18929571, 20855589, 26116789). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Fulgent Genetics, |
RCV002504822 | SCV002814944 | uncertain significance | Hypertrophic cardiomyopathy 10; Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy | 2022-02-01 | criteria provided, single submitter | clinical testing | |
ARUP Laboratories, |
RCV000024457 | SCV003800012 | uncertain significance | not provided | 2022-03-24 | criteria provided, single submitter | clinical testing | The MYL2 c.141C>A; p.Asn47Lys variant (rs199474808; ClinVar Variation ID: 31766) has been observed in at least two probands with hypertrophic cardiomyopathy; however, both we shown to harbor additional clinically suspicious variants in other genes associated with HCM (Andersen 2001, Hougs 2005, Berge 2014). It was also identified in a three month old child whose cause of death was ruled to be SIDS (Methner 2016). In vitro functional studies of the MYL2 p.Asn47Lys variant suggest it may impact MYL2 function; however, the exact in vivo consequences remain unclear at this time (Szczesna-Cordary 2004, Greenberg 2009, Greenberg 2010). Furthermore, this variant has been observed in many ostensibly healthy human populations (Amendola 2015, Andreasen 2013, Whiffin 2017), and is found in the non-Finnish European population with an allele frequency of 0.036% (46/129146 alleles) in the Genome Aggregation Database. The asparagine at codon 47 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.158). Due to conflicting information, the clinical significance of the p.Asn47Lys variant is uncertain at this time. References: Andreasen C et al. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet. 2013 Sep;21(9):918-28. PMID: 23299917 Andersen PS et al. Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations. J Med Genet. 2001 Dec;38(12):E43. PMID: 11748309 Amendola LM et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015 Mar;25(3):305-15. PMID: 25637381 Berge KE and Leren TP. Genetics of hypertrophic cardiomyopathy in Norway. Clin Genet. 2014 Oct;86(4):355-60. PMID: 24111713. Greenberg MJ et al. Regulatory light chain mutations associated with cardiomyopathy affect myosin mechanics and kinetics. J Mol Cell Cardiol. 2009 Jan;46(1):108-15. PMID: 18929571 Greenberg MJ et al. Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17403-8. PMID: 20855589 Hougs L et al. One third of Danish hypertrophic cardiomyopathy patients with MYH7 mutations have mutations (corrected) in MYH7 rod region. Eur J Hum Genet. 2005 Feb;13(2):161-5 PMID: 15483641. Methner DN et al. Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. Genome Res. 2016 Sep;26(9):1170-7. PMID: 27435932 Szczesna-Cordary D et al. Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. J Biol Chem. 2004 Jan 30;279(5):3535-42. PMID: 14594949. Whiffin N et al. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med. 2017 Oct;19(10):1151-1158. PMID: 28518168 |
Leiden Muscular Dystrophy |
RCV000024457 | SCV000045756 | not provided | not provided | 2012-03-26 | no assertion provided | curation | |
Blueprint Genetics | RCV000157368 | SCV000207106 | uncertain significance | Premature ventricular contraction | 2014-11-11 | no assertion criteria provided | clinical testing | |
Forensic Genetics Laboratory, |
RCV000234981 | SCV000263113 | pathogenic | Death in infancy | 2015-03-27 | no assertion criteria provided | clinical testing | |
Stanford Center for Inherited Cardiovascular Disease, |
RCV000024457 | SCV000924883 | uncertain significance | not provided | 2015-12-07 | no assertion criteria provided | provider interpretation |