rs727503276

Positions:

• chr14-23431475-A-G

Variant summary

Our verdict is Pathogenic. Variant got 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.739T>C​(p.Phe247Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F247C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 27 ACMG points.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 571159
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23431474-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181401.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 14-23431475-A-G is Pathogenic according to our data. Variant chr14-23431475-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23431475-A-G is described in Lovd as [Pathogenic]. Variant chr14-23431475-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.739T>C	p.Phe247Leu	missense_variant	9/40	ENST00000355349.4
MYH7	NM_001407004.1	c.739T>C	p.Phe247Leu	missense_variant	8/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.739T>C	p.Phe247Leu	missense_variant	9/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 02, 2016

The p.Phe247Leu variant in MYH7 has been reported in 5 individuals with HCM and segregated with disease in 5 affected relatives from 2 families, including 2 aff ected obligate carriers (Garcia-Castro 2009, Coto 2012, LMM data). This variant was absent from large population studies. Phenylalanine (Phe) at position 247 is highly conserved in mammals and across evolutionarily distant species and the c hange to leucine (Leu) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is es timated to be correct 94% of the time (Jordan 2011). In summary, although additi onal studies are required to fully establish its clinical significance, the p.Ph e247Leu variant is likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2022

The p.F247L variant (also known as c.739T>C), located in coding exon 7 of the MYH7 gene, results from a T to C substitution at nucleotide position 739. The phenylalanine at codon 247 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in an individual with hypertrophic cardiomyopathy (HCM) and his affected relative, as well as reported in individuals from HCM cohorts with limited clinical information provided (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56; Coto E et al. J Mol Diagn, 2012 Sep;14:518-24; Walsh R et al. Genet. Med., 2017 02;19:192-203). Additional segregation with disease has been reported in a family with HCM who had testing performed at outside laboratories (personal communication). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.63	P
Vest4		0.97
MutPred		0.82		Gain of catalytic residue at R249 (P = 2e-04);
MVP		0.94
MPC		2.3
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727503276; hg19: chr14-23900684;