ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3981C>A (p.Asn1327Lys) (rs141764279)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000758038 SCV000564447 uncertain significance Cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.3981C>A (p.Asn1327Lys) variant in MYH7 has been reported in >15 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:15483641; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000059529.5, Invitae ClinVar SCV000254446.5) but has also been identified in 0.01% (12/64286) of European chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). Additionally, this variant was shown not to segregate with disease in 3 affected individuals from 3 families (BS4; PMID:15483641; Partners LMM ClinVar SCV000059529.5). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3; BS4
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000030319 SCV000051008 uncertain significance Primary familial hypertrophic cardiomyopathy 2013-06-24 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000030319 SCV000052986 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-08-08 criteria provided, single submitter clinical testing 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035878 SCV000059529 likely benign not specified 2014-10-08 criteria provided, single submitter clinical testing p.Asn1327Lys in exon 30 of MYH7: This variant has been reported in 1 individual with HCM who carried a second variant of unknown significance, but did not segre gate with disease in 1 affected relative (Houghs 2005, Jensen 2013). It has also been identified by our laboratory in 9 individuals with HCM, but did not segreg ate with disease in 2 individuals from 2 families (LMM unpublished data). In vit ro functional studies provide some evidence that this variant may impact protein function (Wolny 2013). However, in vitro assays may not accurately represent bi ological function. While this variant is rare in the general population (1/8598 European American chromosomes in the NHLBI Exome Sequencing Project, http://evs. gs.washington.edu/EVS/; rs141764279), it appears to be common amongst Ashkenazi Jewish individuals with a prevalence that greatly exceeds that of HCM (5/282 chr omosomes, 1.8%; LMM unpublished data). In summary, the frequency of this variant in the Ashkenazi Jewish population and multiple occurrences of non-segregation with disease indicate this variant is likely benign, although a modifying effect cannot be ruled out.
CSER _CC_NCGL, University of Washington RCV000030319 SCV000190435 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 RCV000588247 SCV000208560 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing The N1327K variant has been reported in multiple individuals with HCM (Hougs et al., 2005; Miller et al., 2013; Xu et al., 2015; Alfares et al., 2015; Lopes et al., 2005). In one study, the N1327K variant in the MYH7 gene was reported to co-segregate with HCM in a single family. However, this family also harbored an A13T variant in MYL2 that was considered pathogenic, and one affected individual only harbored the MYL2 variant (Hougs et al., 2005). Additionally, the proband’s child, who had 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). Furthermore, the N1327K variant in MYH7 has been observed in a healthy control population and reported as a polymorphism (Kapplinger et al., 2014). The N1327K variant is observed in 12/64286 (0.02%) alleles from individuals of European ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The N1327K variant results in a semi-conservative amino acid substitution of a polar, neutral Asparagine residue with a polar, basic Lysine residue. The Asn1327 residue is located in the rod domain of the protein and is highly conserved throughout evolution. In silico analysis predicts that N1327K is damaging to the protein structure/function. Functional assays performed in cultured rat cardiomyocytes suggest that the N1327K substitution results in decreased incorporation of the beta-myosin heavy chain into sarcomeres. However, there was no significant difference in the contractile properties of cardiomyocytes expressing either wild type or mutant beta-myosin heavy chain protein (Wolny et al., 2013). The N1327K variant has been seen in more than 25 probands tested for cardiomyopathy at GeneDx, and none of these probands harbored a known disease-causing pathogenic variant in MYH7 or another HCM gene. In the informative families tested at GeneDx no incidence of non-segregation with disease was observed.
Invitae RCV000588247 SCV000254446 likely benign not provided 2018-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000254007 SCV000319893 likely benign Cardiovascular phenotype 2016-11-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000588247 SCV000696351 uncertain significance not provided 2016-08-04 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588247 SCV000885785 likely benign not provided 2017-08-14 criteria provided, single submitter clinical testing 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588247 SCV000892085 likely benign not provided 2018-09-30 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765159 SCV000896388 uncertain significance Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000758038 SCV000913767 likely benign Cardiomyopathy 2018-10-18 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852700 SCV000995414 likely benign Ventricular fibrillation 2018-10-02 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000588247 SCV000280342 likely benign not provided 2016-11-04 no assertion criteria provided provider interpretation 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.Asn1327Lys) was found in the heterozygous state in one of these patients, and the authors called it a "damaging mutation". This is the only mutation carried by this subject. There is no information about the clinical presentation of this patient in particular. However, 44.6% of patients in this cohort had apical hypertrophy. Laboratory data: In LMM's summary report submitted to ClinVar (Oct 8, 2014), they note they have identified this variant in 9 presumably unrelated cases of HCM, of unreported ancestry. They do not provide data on whether any of these patients had another variant. The variant did not segregate with disease in 2 individuals from 2 families. They also report that the variant appears to be common amongst Ashkenazi Jewish individuals with a prevalence that greatly exceeds that of HCM (5/282 chromosomes, 1.8%; LMM unpublished data); however no clinical information was available for these individuals. GeneDx did not report any internal data in their summary report in ClinVar (Oct 3, 2014). SHaRe: Three sites have reported patients with this variant in the SHaRe registry. Brigham and Women’s reported two probands. One of the probands was a female diagnosed at the age of 66 years, who underwent analysis of 18 genes using LMM's HCM CardioChip. This proband carried an additional variant in the TNNI3 gene (c.373-10T>G), which is classified as benign by both LMM (Apr 11, 2012) and GeneDx (Sep 25, 2012) in ClinVar. The second proband was diagnosed at the age of 18 years, with max wall thickness of 14 mm, who underwent analysis of 11 genes using LMM's HCM CardioChip. These cases are redundant with LMM cases. Stanford University reported two probands. One of the probands was a male diagnosed at the age of 36 years, with max wall thickness of 25 mm, who underwent genetic testing using Correlagen (list of genes tested was not provided). This proband carried an additional variant in MYBPC3 gene (c.3535G>A; p.Glu1179Lys), which is classified as a VUS by LMM (Jul 1, 2014) and CHOE (date of submission not reported), and likely pathogenic by GeneDx (May 21, 2014) in ClinVar. We do not have ancestry on that patient however his name suggests he likely has Jewish ancestry. We have also seen this variant in another patient with HCM diagnosed at 32 years of age who has multiple affected relatives (unconfirmed research data shows segregation with disease in three affected family members). That patient had did not have another variant. We do not have ancestry on that family. University of Michigan reported one proband, who underwent genetic testing with GeneDx's HCM panel. This proband was diagnosed at the age of 18 years, with max wall thickness of 21 mm. This proband carried an additional variant in the PRKAG2 gene (c.866T>C; p.Val289Ala), which is classified as a VUS by GeneDx (Oct 4, 2012) in ClinVar. Additional data: In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts the variant to be tolerated. Functional studies suggest that this variant has a significant effect on alpha-helical content and stability in this region of the protein (Wolny, 2013). The asparagine at codon 1327 is highly conserved, as are neighboring amino acids. No other variants have been reported in association with disease at this codon. Other variants reported in association with disease at nearby codons include: p.Leu1297Val (Millat, 2010), p.Gln1334Ter (Hougs, 2005), and p.Thr1351Met (Girolami, 2006). Frequency in controls, large cohorts unselected for HCM: In total the variant has been seen at least 30 out of ~140,000 individuals from published controls and publicly available datasets that approximate the general population. Five of 141 published controls and 19 out of ~5,000 publicly available controls who are of Ashkenazi Jewish descent carry the variant. Therefore, this variant is too common in the general population, including of this patient’s ethnic group, for it to cause disease. The variant was observed in the following control samples: 1 out of 100 European and 324 multiple ethnicities in Kapplinger (2014), 5 out of 141 Ashkenazi Jewish in LMM (Oct 8, 2014, unpublished, reported in ClinVar). Ng et al. (2013) reported this variant in 1 out of 794 research participants of mixed ancestry, not selected for arrhythmia, cardiomyopathy, or a family history of sudden death, who underwent whole exome sequencing (WES) analysis. The phenotype of this individual is not reported. Of note, there is an over-representation of Ashkenazi Jewish individuals in this cohort (personal communication, L. Beisecker to C. Caleshu). The variant was not observed in the following published control samples: 100 in Hougs (200s5), 250 in Jensen (2013). This variant is present in 24 of 139,301 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino descent. The data includes 126,216 exomes and 15,137 genomes (as of October 21, 2016). Specifically, the variant is present in 19 of 4,980 individuals of Ashkenazi Jewish descent.

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