rs267606908

Positions:

• chr14-23424112-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_Strong PM1 PM2 PS4

This summary comes from the ClinGen Evidence Repository: The c.2717A>G (p.Asp906Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:12081993; PMID:15528230; PMID:16267253; PMID:24510615; Partners LMM ClinVar SCV000059468.5). This variant segregated with disease in 10 affected individuals (PP1_Strong; PMID:12081993; PMID:15528230). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA012936/MONDO:0005045/002

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 7.88

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 Pathogenic. Variant got 12 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.2717A>G	p.Asp906Gly	missense_variant	23/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2717A>G	p.Asp906Gly	missense_variant	22/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2717A>G	p.Asp906Gly	missense_variant	23/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461882 Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000885 Hom.: 0

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2024	Not observed at significant frequency in large population cohorts (gnomAD); A functional study demonstrated that this missense variant caused myosin to move actin at an increased velocity compared to control (PMID: 15528230); 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: 28166811, 27532257, 28606303, 24704860, 29300372, 15528230, 28481356, 29203298, 34542152, 23054336, 12081993, 16267253, 24510615, 26914223, 27247418, 21310275, 28193612, 28241245, 31006259, 32894683, 33087929, 36252119, 36264615, 37652022, 36136372, 36129056) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 06, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 16, 2012	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. MYH7 p.Asp906Gly (c.2717A>G) Given the strong case data, strong segregation data, and absence in controls and the general population (reviewed below) we consider this variant very likely disease causing. The variant has been seen in at least 9 unrelated cases of HCM (not including this patient's family). There is strong segregation data. The Seidmans’ group included a kindred with this variant in a study on diastolic dysfunction in HCM (Ho et al 2002). Of 22 carriers studied, 9 had HCM. Alpert et al (2005) reported a family with this variant with 3 of 13 carriers having HCM. Two siblings from this family married two siblings from another family with HCM and a different MYH7 variant. Two offspring carried both variants and both had HCM. The Seidman group later reported a patient with apical HCM and this variant. His brother died suddenly and had evidence of HCM on autopsy (Arad et al 2005). This appears to be a different family than reported in Ho et al (2002). Ackerman's group observed the variant in 4 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). Those cases are presumably redundant with those in another paper by Ackerman’s group that included 5 HCM patients seen at Mayo or tested Transgenomics (Kapplinger et al 2014). McKenna’s group included a patient with HCM and this variant from their UK cohort in a paper on developmental structural differences in HCM (Captur et al 2014). Per their ClinVar submission, LMM considers the variant pathogenic (SCV000059468). The submission does not include any internal case data. 2 additional entries in ClinVar (OMIM and GeneDx) consider this variant pathogenic. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar score 0.375). Mutationtaster predicts it to be disease causing. The aspartate at codon 906 is not completely conserved across species. Other variants have been reported in association with disease at this codon (p.Asp906Asn (per ClinVar, LMM considers this of uncertain significance (SCV000059466, last reviewed by LMM in 2010)) and nearby codons (p.Asp900Gly, p.Gln907Lys, p.Leu908Val, p.Ile909Val). In total the variant has not been seen in ~6700 published controls and individuals from publicly available population datasets. There is no variation at codon 906 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of October 3rd, 2014). Additionally, there is no variation at this codon in the ExAC dataset, which contains sequence data from ~65,000 individuals of varying ancestries from various exome sequencing cohorts (as of Feb 26, 2015). The variant is listed in dbSNP (rs267606908) with the only submission being disease-related (as of October 3rd, 2014). There is also no variation at this codon listed 1000 genomes (as of October 3rd, 2014). The variant was not observed in the following published control samples: 200 (Bos et al 2014). -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 04, 2021	PS4, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 21, 2022	PP1_strong, PP3, PM1, PM2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 05, 2019	The p.Asp906Gly variant in MYH7 has been identified in >15 individuals with HCM and segregated with disease in >10 affected relatives from 2 families, although reduced penetrance was noted in both families (Ho 2002, Alpert 2005, Arad 2005, Kapplinger 2014, LMM data). It has been identified in 1/246244 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267606908). This low frequency is consistent with the prevalence and penetrance of the condition in the general population. In vitro functional studies provide some evidence that the p.Asp906Gly variant may impact protein function (Alpert 2005). In addition, the p.Asp906Gly variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies, low frequency in the general population and functional evidence. The ACMG/AMP criteria applied: PS4, PM2, PP1_Strong, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 906 of the MYH7 protein (p.Asp906Gly). This variant is present in population databases (rs267606908, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 12081993, 15528230, 24510615, 24704860). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 15528230). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.2717A>G (p.Asp906Gly) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:27532257; PMID:12081993; PMID:15528230; PMID:16267253; PMID:24510615; Partners LMM ClinVar SCV000059468.5). This variant segregated with disease in 10 affected individuals (PP1_Strong; PMID:12081993; PMID:15528230). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PP1_ Strong; PM1; PM2 -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 28, 2023	This missense variant replaces aspartic acid with glycine at codon 906 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). An in vitro functional motility assay has shown that this variant enhances myosin velocity-generating capacity (PMID: 15528230). Another in-vitro functional study has shown that this variant decreased affinity to the S1 binding domain (PMID: 28481356). This variant has been reported in over 20 individuals affected with hypertrophic cardiomyopathy (PMID: 16267253, 24510615, 24704860, 27532257, 33495597, 35026164). It has been shown that this variant segregates with disease in over 10 affected individuals from multiple families (PMID: 12081993, 15528230). This variant has been identified in 1/251460 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 15, 2021	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2021	Variant summary: MYH7 c.2717A>G (p.Asp906Gly) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 252714 control chromosomes. c.2717A>G, has been reported in the literature in to co-segregate with disease multiple individuals affected with Hypertrophic Cardiomyopathy (including apical hypertrophy) but also in unaffected individuals and is considered to have reduced penetrance (example, Ho_2002, Arad_2005, Alpert_2005, Miller_2012, Kapplinger_2014). This variant was also reported in compound heterozygosity with MYBPC3 c.3226_3227insT (p.Asp1076fsX6) and MYH7 c.2722C>G (p.Leu908Val) (Alpert_MYH7_AJPHCP_2005 and internal specimen). Compound heterozygotes (2 variants in MYH7, 2 variants in MYBPC3, or 1 variant each in MYH7 and MYBPC3) are known to be associated with more severe prognosis (example, Alpert_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function where it increased velocity of actin translocation compared to wild-type (example, Alpert_2005). Multiple clinical diagnostic laboratories and an expert panel (ClinGen Cardiomyopathy Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 10, 2015	- -

Hypertrophic cardiomyopathy 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 22, 2019	- -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 28, 2021

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2022

The p.D906G pathogenic mutation (also known as c.2717A>G), located in coding exon 21 of the MYH7 gene, results from an A to G substitution at nucleotide position 2717. The aspartic acid at codon 906 is replaced by glycine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been identified in a number of hypertrophic cardiomyopathy (HCM) cohorts and is reported to co-segregate with disease in two families, although a second segregating MYH7 alteration was noted in one family (Ho CY et al. Circulation. 2002;105:2992-7; Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol. 2005;288:H1097-102; Arad M et al. Circulation. 2005;112:2805-11; Miller EM et al. J Genet Couns. 2013;22:258-67; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Walsh R et al. Genet. Med. 2017;19:192-203; Weissler-Snir A et al. Circ Cardiovasc Imaging. 2017;10:e005311). One in vitro functional assay using isolated myosin from p.D906G carriers found increased velocity of actin translocation compared to wild-type, and a second functional assay suggested that the p.D906G mutation weakens an interaction between the S1 and S2 domains of MYH7 that sequesters myosin heads and prevents them from interacting with actin (Alpert NR et al. Am. J. Physiol. Heart Circ. Physiol. 2005;288:H1097-102; Nag S et al. Nat. Struct. Mol. Biol. 2017;24:525-533). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.15	T
Polyphen		0.42	B
Vest4		0.90
MutPred		0.75		Gain of catalytic residue at I909 (P = 0.0425);
MVP		0.98
MPC		2.1
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.73
gMVP		0.97

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: rs267606908; hg19: chr14-23893321;