rs397516269

chr14-23431426-A-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):c.788T>C(p.Ile263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,824 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I263L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 9.12

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23431427-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1172062.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 14-23431426-A-G is Pathogenic according to our data. Variant chr14-23431426-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 43106.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23431426-A-G is described in Lovd as [Pathogenic]. Variant chr14-23431426-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.788T>C	p.Ile263Thr	missense_variant	9/40	ENST00000355349.4
MYH7	NM_001407004.1	c.788T>C	p.Ile263Thr	missense_variant	8/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.788T>C	p.Ile263Thr	missense_variant	9/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

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: 0.00000410 AC: 6 AN: 1461824 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2013	The Ile263Thr variant in MYH7 has been reported in 7 individuals with HCM and se gregated with disease in >10 affected relatives (Tesson 1997, Tesson 1998, Brito 2003, Richard 2003, Brito 2005, Santos 2012). This variant was not identified i n large population studies. Isoleucine (Ile) at position is highly conserved in mammals and across evolutionarily distant species and the change to threonine (T hr) was predicted to be pathogenic using a computational tool clinically validat ed by our laboratory. This tool's pathogenic prediction is estimated to be corre ct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregat ion studies and absence from controls. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, University of Leuven	Oct 31, 2018	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.788T>C (p.Ile263Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4: PMID:15008060; PMID:9829907; PMID:12707239; PMID:22429680; PMID:20624503; Partners LMM ClinVar SCV000059656.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in 10 affected individuals (PP1_Strong: PMID:15008060; PMID:9829907). 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). 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 pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4, PP1_Strong, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 28, 2023	This missense variant replaces isoleucine with threonine at codon 263 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in greater than 20 individuals affected with hypertrophic cardiomyopathy (9140839, 9829907, 12707239, 15008060, 16335287, 20624503, 21425739, 22429680, 24093860, 24111713, 25611685, 27532257, 29300372, 30297972, 33495596). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29300372). 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	Invitae	Sep 17, 2023	This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 43106). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 9829907, 12707239, 15008060, 21425739, 24093860, 27247418, 27532257). This variant is present in population databases (rs397516269, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the MYH7 protein (p.Ile263Thr). -

Cardiomyopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 08, 2023	This missense variant replaces isoleucine with threonine at codon 263 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in greater than 20 individuals affected with hypertrophic cardiomyopathy (9140839, 9829907, 12707239, 15008060, 16335287, 20624503, 21425739, 22429680, 24093860, 24111713, 25611685, 27532257, 29300372, 30297972, 33495596). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 29300372). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic by the ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel; This variant is associated with the following publications: (PMID: 9829907, 12707239, 27737317, 23074333, 21425739, 16335287, 22429680, 24014347, 20624503, 22857948, 24093860, 9140839, 27532257, 27247418, 25937619, 29300372, 30297972, 31589614, 15008060, 31513939, 33258288, 33586461) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 23, 2015	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.Ile263Thr (c.788T>C) The variant has been seen in at least 5 unrelated cases. The database curated by the Seidman group notes that the variant was first reported in an individual with HCM by Tesson et al (1997) but was mistakenly referred to as p.Ile263Trp (http://genepath.med.harvard.edu/seidman//cg3/muts/MYH7_Ile263Thr.html). The same group did later report a family with two affected members with "I263T", presumably the same family and variant (Tesson et al 1998). Richard et al (2003) reported one HCM patient with this variant in their French cohort. Brito et al (2003, 2005) reported the variant in multiple family members of two unrelated Portugese families. Unfortunately only the abstracts are available so we could not confirm details. Millat et al (2010) observed the variant in one individual with HCM in their French cohort (appears to be distinct from the Richard et al cohort). In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The isoleucine at codon 263 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Ile263Met, which we consider of uncertain significance, probably disease causing) and a nearby codon (p.Gly256Glu). In total the variant has not been seen in ~5700 published controls and publicly available population datasets. There is no variation at codon 263 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5500 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: 100 (Tesson et al 1998), 100 (Richard et al 2003). -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Feb 21, 2017

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Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The p.I263T pathogenic mutation (also known as c.788T>C), located in coding exon 7 of the MYH7 gene, results from a T to C substitution at nucleotide position 788. The isoleucine at codon 263 is replaced by threonine, an amino acid with similar properties. This mutation was identified in multiple individuals with hypertrophic cardiomyopathy and was shown to segregate with disease (Tesson F et al. Hum. Mutat., 1998;12:385-92; Richard P et al. Circulation, 2003 May;107:2227-32; Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46; Santos S et al. BMC Med. Genet., 2012 Mar;13:17; 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; Kelly MA et al. Genet. Med., 2018 03;20:351-359). In some families, reduced penetrance was noted (Tesson F et al. Hum. Mutat., 1998;12:385-92; Brito D et al. Rev Port Cardiol, 2005 Sep;24:1137-46). 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). In addition, 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. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.19	B
Vest4		0.98
MutPred		0.89		Loss of stability (P = 0.0129);
MVP		0.97
MPC		2.3
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.67
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516269; hg19: chr14-23900635;