14-23422190-G-C

Position:

• chr14-23422190-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_000257.4(MYH7):​c.3235C>G​(p.Arg1079Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1079Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.977

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23422189-C-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated cardiomyopathy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3235C>G	p.Arg1079Gly	missense_variant	25/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3235C>G	p.Arg1079Gly	missense_variant	24/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3235C>G	p.Arg1079Gly	missense_variant	25/40	1	NM_000257.4	ENSP00000347507.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 14, 2014

The Arg1079Gly variant in MYH7 has not been reported in individuals with cardiom yopathy or in large population studies. Other variants at this position have bee n reported (Arg1079Gly: Girolami 2010, Waldmuller 2011, LMM unpublished data; Ar g10479Trp: dbSNP rs192722540), though their significance is unclear. Arginine at position 1079 is not conserved in mammals or evolutionarily distant species, th ough the change to glycine (Gly) was predicted to be pathogenic using a computat ional tool clinically validated by our laboratory. This tool's pathogenic predic tion is estimated to be correct 94% of the time (Jordan 2011). At this time, add itional information is needed to fully assess the clinical significance of the A rg1079Gly variant. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2014

p.Arg1079Gly (CGG>GGG): c.3235 C>G in exon 25 of the MYH7 gene (NM_000257.2). The R1079G mutation in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. R1079G results in a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The R1079 residue is conserved across mammals. A mutation in this same residue (R1079Q) has been reported in association with cardiomyopathy, and has been observed at GeneDx in one affected patient referred for HCM testing, supporting the functional importance of this residue. The R1079G mutation 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. In silico algorithms are not consistent in their predictions but at least two concur that R1079G is damaging to the protein structure/function. In summary, R1079G in the MYH7 gene is interpreted as a likely disease-causing mutation. The variant is found in HCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
CardioboostCm	Benign	0.0067
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.083	T
Polyphen		0.050	B
Vest4		0.50
MutPred		0.57		Loss of stability (P = 0.0124);
MVP		0.78
MPC		0.86
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.52
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs192722540; hg19: chr14-23891399;