rs367546859

Variant names:

• chr14-23420993-C-G
• rs367546859
• NM_000257.4:c.3301G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-23420993-C-G
• chr14-23420993-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000257.4(MYH7):​c.3301G>C​(p.Gly1101Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,240 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1101S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.20
• Publications: 0 publications found

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]

MYH7 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1S

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• MYH7-related skeletal myopathy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• myopathy, myosin storage, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• myopathy, myosin storage, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myopathy 7A, myosin storage, autosomal dominant

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ebstein anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyaline body myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• left ventricular noncompaction

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294572 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the MYH7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 341 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 3.9329 (above the threshold of 3.09). Trascript score misZ: 6.7889 (above the threshold of 3.09). GenCC associations: The gene is linked to myopathy, myosin storage, autosomal recessive, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, Ebstein anomaly, hyaline body myopathy, left ventricular noncompaction, hypertrophic cardiomyopathy 1, dilated cardiomyopathy 1S, dilated cardiomyopathy, congenital heart disease, familial isolated dilated cardiomyopathy, myopathy, myosin storage, autosomal dominant, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.3301G>C	p.Gly1101Arg	missense	Exon 26 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.3301G>C	p.Gly1101Arg	missense	Exon 25 of 39	NP_001393933.1	P12883

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.3301G>C	p.Gly1101Arg	missense	Exon 26 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.3301G>C	p.Gly1101Arg	missense	Exon 26 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.3301G>C	p.Gly1101Arg	missense	Exon 26 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460240 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726432

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4446

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60240

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
CardioboostCm	Benign	0.0029
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.030
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.030	D
Sift4G	Benign	0.54	T
Polyphen		0.11	B
Vest4		0.38
MutPred		0.51		Gain of MoRF binding (P = 0.0193)
MVP		0.93
MPC		1.1
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.35
gMVP		0.79
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs367546859; hg19: chr14-23890202;