rs730880742

chr14-23424984-T-Achr14-23424984-T-Cchr14-23424984-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):c.2464A>T(p.Met822Leu) 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 Conflicting classifications of pathogenicity (no stars). 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. M822I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.61

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.

• PS1: Transcript NM_000257.4 (MYH7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 181370
• PM1: In a hotspot region, there are 8 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 chr14-23424983-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1507515.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843
• PP5: Variant 14-23424984-T-A is Pathogenic according to our data. Variant chr14-23424984-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181188.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2464A>T	p.Met822Leu	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2464A>T	p.Met822Leu	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2464A>T	p.Met822Leu	missense_variant	22/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 06, 2017

The M822L likely pathogenic variant due to the nucleotide substitution c.2464 A>T in the MYH7 gene has been previously reported in one individual with HCM (Lopes et al., 2015). The same amino acid substitution due to a different nucleotide change (M822L, c.2464 A>C) has also been previously reported in association with HCM (Fujino et al., 2013). The M822L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While M822L is a conservative amino acid substitution, it occurs at a position that is conserved across species. In addition, the majority of in silico tools also predict this variant is probably damaging to the protein structure/function. Moreover, a missense variant in the same residue (M822V) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), further supporting the functional importance of this residue of the protein. Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required. -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 822 of the MYH7 protein (p.Met822Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12820698, 19149795, 20975235, 25351510). ClinVar contains an entry for this variant (Variation ID: 181188). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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). This variant disrupts the p.Met822 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12881443). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.048
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.56
Sift	Benign	0.050	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.75
MutPred		0.64		Gain of catalytic residue at W827 (P = 0.0143);
MVP		0.89
MPC		0.94
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.52
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs730880742; hg19: chr14-23894193;