chr14-23431468-C-T

Position:

• chr14-23431468-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.746G>A​(p.Arg249Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 7.74

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 17 ACMG points.

• PM1: In a strand (size 8) in uniprot entity MYH7_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 14-23431468-C-T is Pathogenic according to our data. Variant chr14-23431468-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23431468-C-T is described in Lovd as [Pathogenic]. Variant chr14-23431468-C-T is described in Lovd as [Pathogenic]. Variant chr14-23431468-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.746G>A	p.Arg249Gln	missense_variant	9/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.746G>A	p.Arg249Gln	missense_variant	8/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.746G>A	p.Arg249Gln	missense_variant	9/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Apr 08, 2019	PS2, PS4, PM2, PP1, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 23, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29300372.). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014088). Different missense changes at the same codon (p.Arg249Gly, p.Arg249Leu) have been reported to be associated with MYH7 related disorder (ClinVar ID: VCV000635223 / PMID: 24691700). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	MYH7: PM1, PM2, PP2, PS3:Supporting, PS4:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies demonstrate abnormal ATPase activity and decreased muscle contractibility (Roopnarine et al., 1998; Adhikari et al., 2019; Bell et al., 2019); This variant is associated with the following publications: (PMID: 24093860, 10065021, 27247418, 10521296, 25611685, 23283745, 23396983, 24805292, 30206291, 30685992, 28481356, 31980526, 24298987, 9826622, 1944483, 23233322, 11133230, 12975413, 26914223, 27532257, 7662452, 12707239, 7731997, 23054336, 22112859, 23549607, 29212898, 30767072, 30950055, 31397097, 31513939, 31213605, 31019026, 27841901, 33407484, 29300372) -
Pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Oct 08, 2014	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.Arg249Gln (c.746G>A). Based on the data reviewed below we consider this variant very likely disease causing. The variant has been seen in at least 11 unrelated cases of HCM with strong segregation data. The Seidman group first reported the variant segregating with HCM in eight family members with a Lod score of 4.0 (Rosenzweig et al 1991). An additional family reported by Posen et al (1995) also had 8 affected family members with the variant. Arbustini et al (1998) reported a family in which 7 family members with HCM all had both p.Arg249Gln and a mitochondrial variant (tRNAIle A4300G). They also reported an individual with HCM and a de novo p.Arg249Gln variant (he also had an inherited mitochondrial variant). Paternity was confirmed with molecular studies. He had no family history of HCM. Greber-Platzer et al (2001) reported the variant occurring de novo in a child with severe infantile HCM. Her parents and siblings were reported as clinically normal, though it is unclear if they had cardiac evaluations or if paternity was confirmed. Richard et al (2003) reported the variant in three unrelated cases of HCM from their French cohort. Woo et al (2003) reported the variant in three individuals with HCM from a Canadian cohort. Notably, the extent of the decrease in myosin motor activity for MHC Arg403Gln (70–80%), Arg453Cys (70–80%), Arg249Gln (40–50%) and Val606Met (10–15%) correlates well with the cumulative survival rates at 50 years for these mutations (36, 34, 79 and 94%, respectively) [7,45]. Also, the decrease in actin-activated myosin–ATPase rates of rat myosins with the Arg249Gln, Arg403Gln and Val606Met mutations was found to correlate with the severity of clinical phenotype (moderate, severe and mild, respectively) [100]. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging while SIFT predicts it to be deleterious. The arginine at codon 249 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.Arg243His, p.Phe244Leu, p.Lys246Gln, p.Gly256Glu). We could find no other disease associated variants at codon 249. In total the variant has not been seen in ~5211 published controls and publicly available population datsets. There is no variation at codon 249 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 111 individuals (Arbustini et al 1998), 100 individuals (Richard et al 2003). Early studies on this variant did not report control data. -

Hypertrophic cardiomyopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2014	The p.Arg249Gln variant in MYH7 has been reported in >10 individuals with hypert rophic cardiomyopathy (HCM), including 2 de novo occurrences, and segregated wit h disease in >30 affected relatives from 3 families (Rosenzweig 1991, Watkins 19 92, Posen 1995, Arbustini 1998, Greber-Platzer 2001, Richard 2003, Woo 2003, Kas sem 2013). Additionally, this variant has been reported by other clinical labor atories in ClinVar (Variation ID: 14088) and was absent from large population st udies. Arginine (Arg) at position 249 is highly conserved in mammals and the ch ange to glutamine (Gln) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). Moreover, this variant is located in the head domain of the MYH7 protein, where studies have shown that va riants in this region have an increased probability for causing disease (Walsh 2 017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon segregation studies, de novo occurrences, and absence from controls. ACMG/AMP criteria applied: PS4, PM6_Strong, PP1_Strong, PM2, PM1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 249 of the MYH7 protein (p.Arg249Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or left ventricular non-compaction (PMID: 1944483, 7662452, 10065021, 23549607, 24691700, 25351510, 27532257, 27841901). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14088). 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: 9826622). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Dec 13, 2017	This variant is well described in patients with hypertrophic cardiomyopathy (PMID: 1430197, 12707239, 12975413) and has been reported by multiple clinical laboratories as pathogenic in the ClinVar database (Variation ID 14088). The p.Arg249Gln variant is located in exon 9 at the active site of the beta-myosin heavy chain functional domain (PMID: 12975413). Functional studies for the p.Arg249Gln variant have shown impairment of ATPase activity and disruption of the actomyosin interaction site in rat models (PMID: 9826622). This variant is absent from population databases, thus it is presumed to be rare. Based on the combined evidence, the p.Arg249Gln variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 09, 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 31, 2018

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The p.R249Q pathogenic mutation (also known as c.746G>A), located in coding exon 7 of the MYH7 gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by glutamine, an amino acid with highly 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 mutation has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), including two de novo cases, and has segregated with disease in multiple families (e.g., Rosenzweig A et al. N. Engl. J. Med. 1991;325:1753-60; Posen BM et al. Br Heart J. 1995;74:40-6; Arbustini E et al. Heart. 1998;80:548-58; Greber-Platzer S et al. J. Mol. Cell. Cardiol., 2001;33:141-8; Otsuka H et al. Circ. J. 2012;76:453-61; Kassem HSh et al. J Cardiovasc Transl Res. 2013;6:65-80; Marsiglia JD et al. Am. Heart J. 2013;166:775-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. 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	0.98
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.78		Gain of catalytic residue at A254 (P = 0);
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3218713; hg19: chr14-23900677; COSMIC: COSV62516493;