14-23418398-G-T

Position:

• chr14-23418398-G-T

Variant summary

Our verdict is Likely benign. Variant got -12 ACMG points: 0P and 12B. BA1 BS4

This summary comes from the ClinGen Evidence Repository: The c.3981C>A (p.Asn1327Lys) variant in MYH7 has been identified in 0.16% (FAF 95% CI; 24/10156) of Ashkenazi Jewish chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; Kelly 2018 PMID:29300372). Based on criteria selected, this variant should be classified as benign; however, the expert panel felt that since frequency in other populations is not as elevated as in the Ashkenazi Jewish population, it warrants adjusting in the final classification to likely benign. Therefore, this variant is classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1 with expert panel adjustment. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014310/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:14
• Conservation: PhyloP100: -3.31

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -12 ACMG points.

• BS4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3981C>A	p.Asn1327Lys	missense_variant	30/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3981C>A	p.Asn1327Lys	missense_variant	29/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3981C>A	p.Asn1327Lys	missense_variant	30/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000113 AC: 28 AN: 247224 Hom.: 0 AF XY: 0.0000971 AC XY: 13 AN XY: 133948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00243

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000461 AC: 67 AN: 1454010 Hom.: 0 Cov.: 31 AF XY: 0.0000512 AC XY: 37 AN XY: 722036

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000813

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6 Benign:14

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:4

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 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2024	See Variant Classification Assertion Criteria. -
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. -
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. -

Cardiomyopathy Benign:3

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 18, 2018	- -

Primary familial hypertrophic cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Hypertrophic cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Apr 24, 2020	The c.3981C>A (p.Asn1327Lys) variant in MYH7 has been identified in 0.16% (FAF 95% CI; 24/10156) of Ashkenazi Jewish chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BA1; Kelly 2018 PMID:29300372). Based on criteria selected, this variant should be classified as benign; however, the expert panel felt that since frequency in other populations is not as elevated as in the Ashkenazi Jewish population, it warrants adjusting in the final classification to likely benign. Therefore, this variant is classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1 with expert panel adjustment. -

Myosin storage myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hypertrophic cardiomyopathy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 08, 2014

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. -

MYH7-related skeletal myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Ventricular fibrillation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Oct 02, 2018

- -

MYH7-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2019

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.91	T
Polyphen		0.53	P
Vest4		0.92
MutPred		0.58		Gain of ubiquitination at N1327 (P = 0.0267);
MVP		0.94
MPC		0.97
ClinPred		0.26	T
GERP RS		-0.39
Varity_R		0.25
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141764279; hg19: chr14-23887607;