14-23417597-C-T

Variant names:

• chr14-23417597-C-T
• rs397516207
• NM_000257.4:c.4259G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):​c.4259G>A​(p.Arg1420Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000685 in 1,460,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1420W) has been classified as Likely pathogenic. The gene MYH7 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.96
• Publications: 11 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]

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Specifications for MYH7 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a helix (size 64) in uniprot entity MYH7_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23417598-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 43003.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 hypertrophic cardiomyopathy 1, Ebstein anomaly, left ventricular noncompaction, hypertrophic cardiomyopathy, dilated cardiomyopathy 1S, MYH7-related skeletal myopathy, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, myopathy, myosin storage, autosomal recessive, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal dominant, hyaline body myopathy, familial isolated dilated cardiomyopathy, congenital heart disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 14-23417597-C-T is Pathogenic according to our data. Variant chr14-23417597-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4259G>A	p.Arg1420Gln	missense	Exon 31 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4259G>A	p.Arg1420Gln	missense	Exon 30 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.*2C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4259G>A	p.Arg1420Gln	missense	Exon 31 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4259G>A	p.Arg1420Gln	missense	Exon 31 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4259G>A	p.Arg1420Gln	missense	Exon 31 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460396 Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4 AN XY: 726518

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86188

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4514

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60278

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000267 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hypertrophic cardiomyopathy (3)
3	-	-	not provided (3)
2	-	-	Cardiomyopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Hypertrophic cardiomyopathy 1 (1)
1	-	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.67		Gain of catalytic residue at L1421 (P = 0.0198)
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.94
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs397516207; hg19: chr14-23886806; COSMIC: COSV62518491; COSMIC: COSV62518491;