chr14-23417174-G-A

Variant names:

• chr14-23417174-G-A
• rs45544633
• NM_000257.4:c.4498C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000257.4(MYH7):​c.4498C>T​(p.Arg1500Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 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 (★★). ClinVar reports functional evidence for this variant: "SCV000199112: "In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function." (Armel 2010, Wolny 2013); SCV004844777: Experimental studies have shown that this missense change causes severely decreased thermodynamic stability and affects filament assembly (PMID:19854198).; SCV000284279: Experimental studies have shown that this missense change affects MYH7 function (PMID:19854198).; SCV000737223: "In vitro studies suggest that this alteration has an impact on filament formation; however, the same effect was not reproduced in vivo (Armel TZ et al. J. Mol. Cell. Cardiol., 2010 May;48:1007-13; Buvoli M et al. J. Mol. Biol. 2012;415:807-18; Wolny M et al. J. Biol. Chem., 2013 Nov;288:31952-62)."; SCV004359533: "In vitro functional studies provide some evidence that this variant may destabilize the MYH7 protein (PMID:19854198, 22155079, 24047955)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1500Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 0.238
• Publications: 15 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

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000199112: "In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function." (Armel 2010, Wolny 2013); SCV004844777: Experimental studies have shown that this missense change causes severely decreased thermodynamic stability and affects filament assembly (PMID: 19854198).; SCV000284279: Experimental studies have shown that this missense change affects MYH7 function (PMID: 19854198).; SCV000737223: "In vitro studies suggest that this alteration has an impact on filament formation; however, the same effect was not reproduced in vivo (Armel TZ et al. J. Mol. Cell. Cardiol., 2010 May;48:1007-13; Buvoli M et al. J. Mol. Biol. 2012;415:807-18; Wolny M et al. J. Biol. Chem., 2013 Nov;288:31952-62)."; SCV004359533: "In vitro functional studies provide some evidence that this variant may destabilize the MYH7 protein (PMID: 19854198, 22155079, 24047955)."
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 uncertain in NM_000257.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-23417173-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.952
• PP5: Variant 14-23417174-G-A is Pathogenic according to our data. Variant chr14-23417174-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 164284.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.4498C>T	p.Arg1500Trp	missense	Exon 32 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4498C>T	p.Arg1500Trp	missense	Exon 31 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.652-38G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4498C>T	p.Arg1500Trp	missense	Exon 32 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4498C>T	p.Arg1500Trp	missense	Exon 32 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4498C>T	p.Arg1500Trp	missense	Exon 32 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000535 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cardiomyopathy (2)
2	-	-	Cardiovascular phenotype (2)
2	-	-	Primary dilated cardiomyopathy (2)
1	-	-	Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		0.24
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.65		Loss of methylation at K1499 (P = 0.0452)
MVP		0.90
MPC		1.4
ClinPred		1.0	D
GERP RS		0.85
Varity_R		0.70
gMVP		0.76
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs45544633; hg19: chr14-23886383; COSMIC: COSV62516913; COSMIC: COSV62516913;