rs397516208

Variant names:

• chr14-23417580-C-T
• rs397516208
• NM_000257.4:c.4276G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-23417580-C-T
• chr14-23417580-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS4_Supporting PM2 PP3

This summary comes from the ClinGen Evidence Repository: The NM_000257.4 (MYH7): c.4276G>A (p.Glu1426Lys) variant has been identified in 5 individuals with DCM (PS4_Supporting; Villard 2005 PMID:1576978; Shipman 2011 PMID:21482996; Vikhorev 2017 PMID:29093449; GeneDx pers. comm.; LMM pers. comm.), including as a de novo occurrence in 1 infant with an additional variant in a cardiomyopathy-associated gene (GeneDx pers. comm.) and in 1 individual with HCM (Walsh 2017 PMID:27532257; OMGL pers. comm.). Because of the additional variant observed in the individual with the de novo occurrence, the PM6 criterion was not applied. This variant has also been reported in 1 individual with LVNC and reduced ejection fraction and in 1 individual with familial nondilated cardiomyopathy and their child with LVNC (Ambry pers. comm.; Invitae pers. comm). This variant segregated with disease in 2 affected relatives with DCM from 1 family (Villard 2005 PMID:1576978); however, this data is currently insufficient to establish co-segregation with disease and apply PP1. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014743/MONDO:0005021/002

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:3
• Conservation: PhyloP100: 7.69
• Publications: 12 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: Uncertain_significance. The variant received 4 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

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.4276G>A	p.Glu1426Lys	missense	Exon 31 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.4276G>A	p.Glu1426Lys	missense	Exon 30 of 39	NP_001393933.1	P12883
	MHRT	NR_126491.1		n.861C>T		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.4276G>A	p.Glu1426Lys	missense	Exon 31 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.4276G>A	p.Glu1426Lys	missense	Exon 31 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.4276G>A	p.Glu1426Lys	missense	Exon 31 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
1	-	-	Dilated cardiomyopathy 1S (1)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)
1	-	-	Primary familial dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.77		Gain of MoRF binding (P = 0.0045)
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.53
gMVP		0.99
Mutation Taster		=0/100	disease causing

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: rs397516208; hg19: chr14-23886789; COSMIC: COSV62519182; COSMIC: COSV62519182;