rs730880899

chr14-23424904-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):c.2544G>C(p.Glu848Asp) variant causes a missense change involving the alteration of a non-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 variant affecting the same amino acid position, but resulting in a different missense (i.e. E848G) 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:3
• Conservation: PhyloP100: 1.22

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 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr14-23424905-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 177758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 14-23424904-C-G is Pathogenic according to our data. Variant chr14-23424904-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181374.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.2544G>C	p.Glu848Asp	missense_variant	22/40	ENST00000355349.4
MYH7	NM_001407004.1	c.2544G>C	p.Glu848Asp	missense_variant	21/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.2544G>C	p.Glu848Asp	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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 14, 2015	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu848Asp in MYH7 has not been previously reported in individuals with cardiomyopathy or in large population studies. The glutamate residue (Glu) at position 848 is high ly conserved in mammals and across evolutionarily distant species, and the chang e to aspartic acid (Asp) was predicted to be pathogenic using a computational to ol clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, while there i s some suspicion for a pathogenic role, the clinical significance of the p.Glu84 8Asp variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2016	A variant of uncertain significance has been identified in the MYH7 gene. The E848D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, this variant has previously been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, but segregation data is absent. In addition, this variant has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000272040.1, SCV000280327.1; Landrum et al., 2016). The E848D 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. This substitution occurs at a position that is conserved across species and 2/3 in silico prediction programs predict this variant is probably damaging to the protein structure/function. However, the E848D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge no studies have been performed to determine the functional effect of the E848D variant.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Nov 29, 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. p.Glu848Asp (c.2544G>C) in MYH7 This is a conservative amino acid substitution with a hydrophilic Glutamine replaced with a hydrophilic Asparagine. Conservation analysis indicates that Glutamine is highly conserved at this position and in silico algorithms (Adzhubei et al 2010) predict the amino acid change to be probably damaging to protein structure/function. Missense variants in nearby codons (Lys847Glu, Ala850Asp, and Ala850Thr) have been reported in association with cardiomyopathy thus indicating a functional significance of this region of beta myosin heavy chain protein. In total p.Glu848Asp has not been observed in ~5500 individuals of varying ancestry. GeneDx reports the absence of the variant in 200 presumably healthy controls of both Caucasian and African American ancestry. The variant is not currently listed in NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/). This dataset includes variant calls on approximately ~5300 well phenotyped individuals of Caucasian and African American descent (as of January 2012). The variant is not reported in dbSNP or 1000 Genomes (As of January 2012). -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 29, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Glu848 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 181374). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30847666, 33673806). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 848 of the MYH7 protein (p.Glu848Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
CardioboostCm	Uncertain	0.76
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	4.5	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.33		Gain of MoRF binding (P = 0.1103);
MVP		0.88
MPC		2.0
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.58
gMVP		0.98

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: rs730880899; hg19: chr14-23894113; COSMIC: COSV62522964;