Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 14, 2017 | The p.Asn1327Lys variant (rs141764279) has been previously reported to segregate with disease in a family with hypertrophic cardiomyopathy (Hougs 2005 and Jensen 2013); however, three out of four of the affected individuals also carried a variant in MYL2. In addition, this variant has been identified in cohorts of unrelated, presumably healthy individuals (Ng 2013 and Kapplinger 2014). This variant is listed in the Genome Aggregation Database (gnomAD) browser with a frequency of 0.2% in Ashkenazi Jewish individuals (identified in 20 out of 9950 chromosomes), which is higher than expected for a pathogenic variant in MYH7. It is listed in the ClinVar database (Variation ID: 36641) as likely benign according to multiple labs, including a ClinGen expert panel. Functional data demonstrated that the p.Asn1327Lys mutant MYH7 protein expressed in adult rat cardiomyocytes had reduced incorporation into sarcomeres; however, the mutant protein did not alter contractile properties, raising questions about the physiological relevance of this reduced incorporation (Wolny 2014). Based on these observations, the p.Asn1327Lys variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2016 | Variant summary: The MYH7 c.3981C>A (p.Asn1327Lys) variant involves the alteration of a non-conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Asn1327 is conserved across species and is located in the conserved myosin rod tail domain of the protein. No other variants have been reported in association with disease at this codon. Other missense variants reported in association with HCM at nearby codons include p.L1297Q (PMID: 25132132), p.L1297V (PMID: 20800588), and p.A1332T (PMID: 21750094). Functional studies suggest that N1327K has a significant effect on alpha-helical content and stability in this region of the protein, and led to decreased incorporation of myosin into thick filaments when overexpressed in adult cardiomyocytes (Wolny, 2013), but the clinical implication of these observations are uncertain. This variant was found in 14/118622 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001867 (12/64286). This frequency is less than the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0010005; 1/1000), thus it is unclear if this is a benign polymorphism based on ExAC and published control data alone. However, LMM reports the variant to be common amongst Ashkenazi Jewish individuals with a prevalence that greatly exceeds that of HCM (5/282 chromosomes, 1.8%; LMM unpublished data). The N1327K mutation in the MYH7 gene has been reported to partially co-segregate with HCM in a single family. In this family, another variant, possibly associated with HCM (c.37G>A [p.A13T] in the MYL2 gene; LCA classified as VUS in 2012 and conflicting interpretations in ClinVar) was also present in the proband (LVH thickness of 20mm). An individual carrying MYL2 c.37G>A in isolation had a LVH thickness of 23mm, while an individual carrying MYH7 in isolation had a LVH thickness of 14mm (Hougs, 2005). According to the American Heart Association 2011 guidelines (PMID: 22093723), a MaxLVD of 14 mm does not meet LVH thickness cutoff diagnostic value of 15mm, suggesting that MYH7 c.3981C>A in isolation may not be causative; however, it should be noted that patients who are genotype positive may be phenotypically negative without overt hypertrophy. A twelve year follow-up study on the son of the proband in this family (carried both the MYL2 and MYH7 variants) showed no signs of hypertrophy in the intervening years, however, at 22 years old upon completion of the follow-up study, he was less than the average age of onset (30 years old), and thus, he may develop the disease later in his life (Jensen, 2013). Additionally, authors do not unequivocally state that N1327K is pathogenic. Furthermore, of significance is a ClinVar entry by LMM that reports the variant to have been identified in 9 individuals with HCM, but did not segregate with disease in 2 individuals from 2 families (LMM unpublished data). The variant was reported in ClinVar by multiple clinical diagnostic laboratories with conflicting classifications from VUS to Likely Benign. Taken together and based on the lack of co-segregation with disease in multiple families, this variant was classified as Variant of Uncertain Clinical Significance (VUS) until additional information is available. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 18, 2023 | Showed possible segregation with disease in one family that also harbored a reportedly pathogenic variant in the MYL2 gene; however, one affected relative harbored only the MYL2 variant (Hougs et al., 2005), and one relative who harbored both the MYH7 variant and the MYL2 variant was reported to have a normal cardiac phenotype after a 12 year follow-up (Jensen et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional assays performed in cultured rat cardiomyocytes suggest that this variant results in decreased incorporation of the beta-myosin heavy chain into sarcomeres; however, no significant difference in contractile properties was observed (Wolny et al., 2013); This variant is associated with the following publications: (PMID: 23299917, 23197161, 28166811, 29300372, 33190526, 30297972, 23861362, 15483641, 23054336, 24510615, 26573135, 25637381, 23785128, 25611685, 25961035, 21310275, 25351510, 19035361, 27247418, 27153395, 30095857, 24047955, 34542152) - |
Likely benign, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Nov 04, 2016 | Given the co-occurrence of another variant in several cases, the failure to segregate, and the apparent presence of the variant at an appreciable frequency in multiple general population samples, including individuals of Ashkenazi Jewish ancestry, (reviewed below) we consider this variant probably benign and do not consider it appropriate for testing family members ("predictive genetic testing"). Note this includes this patient's data. Summary: -Seen in at least 14 presumably unrelated cases of HCM (2 published, 12 unpublished). -In 3 of 6 cases who had sequencing of at least MYH7, MYBPC3, and TNNT2 another variant (VUS or likely pathogenic) was present. - One proband carried a second variant in MYL2 (c.37G>A; p.Ala13Thr) (ClinVar: likely pathogenic by GeneDx (Aug 12, 2014) and a VUS by LMM (Mar 16, 2009)) - 36-year-old female proband with LVWT of 25 mm carried a second variant in MYBPC3 (c.3535G>A; p.Glu1179Lys) (ClinVar: a VUS by LMM (Jul 1, 2014) and CHOE (date of submission not reported), and likely pathogenic by GeneDx (May 21, 2014)) - 18-year-old proband with LVWT of 21 mm carried a second variant in PRKAG2 (c.866T>C; p.Val289Ala) (ClinVar: a VUS by GeneDx (Oct 4, 2012)) -Segregation data: LMM reports that in two families the variant failed to segregate with disease in another affected family member. A reported case is suspicious for failure to segregate (Houghs et al) -The variant is too common in Ashkenazi Jewish reference samples (ex. 19 of 4,800 individuals in gnomAD). Published cases: Hougs et al. (2005) and Jensen et al. (2013) reported this variant in 1 out of 92 European patients with HCM that were cared for in Copenhagen University Hospital in Copenhagen, Denmark, who underwent analysis of the MYH7, MYBPC3, TPM1, TNNT2, TNNI3, ACTC, MYL2, and MYL3 genes. The proband is a 46-year-old male with LVWT of 20 mm, who needed percutaneous transluminal septal myocardial ablation for treatment. This proband carried an additional variant in MYL2 gene (c.37G>A; p.Ala13Thr), which is classified as likely pathogenic by GeneDx (Aug 12, 2014) and a VUS by LMM (Mar 16, 2009) per ClinVar. He had a 49-year-old affected brother with LVWT of 14 mm, who carried the MYH7 variant, and was obese and hypertensive and thus may have had secondary hypertrophy and not HCM. His affected fraternal twin sister, who had LVWT of 23 mm, carried the MYL2 mutation, but did not carry the MYH7 variant; his deceased mother was affected, and was an obligate carrier for both of the variants; his 10-year-old unaffected son also carried both for the variants. No additional phenotypic information or variants were provided by the authors. Miller et al. (2012) reported this variant in 1 out of 46 patients with HCM that were cared for in Cincinnati Children's Hospital Medical Center in Cincinnati, OH, who underwent analysis of MYH7, TNNT2, TPM1, MYBPC2, TNNI3, MYL2, MYL3, ACTC, TTR, TNNC1, CAV3, LAMP2, GLA, PRKAG2, MTTC, MTTI, MTTK, LMNA, ZAS/LDB3, DES, SGCD, PLN, ACTC1, TNNI2, TAZ, TTR, MTTL1, MTTQ, MTTH, MTTS1, MTTS2, MTND1, MTND5, and MTND6 genes. Ancestry of the patient was not reported. The study cohort included ~79% non-Hispanic Caucasian, 12 % Black, <2 % Asian, and 7 % Hispanic patients. No additional phenotypic information or variants were provided by the authors. Xu et al. (2015) used whole exome sequencing (WES) to query the genetic cause of patients with "sporadic" HCM. Study was conducted on 74 Han Chinese patients with HCM who did not have mutations in the 8 sarcomere genes: MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3. The genes that were included are not as established in their cause of HCM: RYR2,CALM3, JPH2, PLN, SRI, CALR3 and CASQ2,AGK, COX15, GLA, FXN, PRKAG2, MRPL3, LAMP2, TAZ and SLC25A4. 94% of the targeted regions were covered at least 4x. The authors analyzed novel or rare variants in known HCM genes. Mutations in MYH7 were found in 2 patients even though they should have been filtered out. N1327K (p.Asn13 - |