rs730880911

chr14-23417202-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):c.4470G>C(p.Glu1490Asp) 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. E1490G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.469

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]

MHRT (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 14-23417202-C-G is Pathogenic according to our data. Variant chr14-23417202-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 181390.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.4470G>C	p.Glu1490Asp	missense_variant	32/40	ENST00000355349.4
MHRT	NR_126491.1	n.652-10C>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
MYH7	NM_001407004.1	c.4470G>C	p.Glu1490Asp	missense_variant	31/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4470G>C	p.Glu1490Asp	missense_variant	32/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Jul 12, 2011

This mutation is denoted p.Glu1490Asp (E1490D) at the protein level and c.4470 G>C at the cDNA level. The Glu1490Asp variant in the MYH7 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Although Glu1490Asp results in a conservative amino acid substitution of one negatively charged, polar amino acid with another, it occurs at a position that is highly conserved throughout evolution. Additionally, in silico analysis predicts Glu1490Asp to be probably damaging to the protein structure/function. Mutations in nearby codons (Tyr1488Cys, Ser1491Cys, Glu1496Ala) have been reported in association with left ventricular non-compaction and HCM, further supporting the functional importance of this region of the protein. Glu1490Asp was not observed in up to 400 alleles from control individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphism in these populations. In summary, while the Glu1490Asp variant is a good candidate for a disease-causing mutation, we cannot unequivocally determine whether Glu1490Asp is a disease-causing mutation or a rare benign variant. The variant is found in HCM panel(s). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2015

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu1490As p variant in MYH7 has not been previously reported in individuals with cardiomyo pathy and was absent from large population studies. Glutamic acid (Glu) at posit ion 1490 is highly conserved in mammals and across evolutionarily distant specie s and the change to aspartic acid (Asp) was predicted to be pathogenic using a c omputational tool 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 is some suspicion for a pathogenic role, the clinical significance of the p.Glu1490Asp variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.53		Loss of methylation at K1485 (P = 0.2045);
MVP		0.96
MPC		1.5
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.58
gMVP		0.81

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: rs730880911; hg19: chr14-23886411;