rs121913654

Variant names:

• chr14-23415176-A-G
• rs121913654
• NM_000257.4:c.5378T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-23415176-A-G
• chr14-23415176-A-T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_000257.4(MYH7):​c.5378T>C​(p.Leu1793Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000280365: By functional in vitro analysis, Armel and Leinwand (2009) showed that the L1793P mutation does not alter the secondary structure of the protein or the ability to form alpha-helical coiled coils compared to wildtype, but does decrease thermodynamic stability compared to wildtype. The L1793P mutation decreases the ability of LMM to assemble into an LMM rod (akin to forming thick filaments), presumably because of the increased instability of the molecule: Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly into filaments.". Synonymous variant affecting the same amino acid position (i.e. L1793L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.10
• Publications: 16 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000258444 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000280365: By functional in vitro analysis, Armel and Leinwand (2009) showed that the L1793P mutation does not alter the secondary structure of the protein or the ability to form alpha-helical coiled coils compared to wildtype, but does decrease thermodynamic stability compared to wildtype. The L1793P mutation decreases the ability of LMM to assemble into an LMM rod (akin to forming thick filaments), presumably because of the increased instability of the molecule: Although the paracrystals formed were similar to wildtype, they were more susceptible to proteolytic cleavage. The authors suggested that the L1793P mutation destabilized the dimer interface under conditions similar to those found in vivo, which affects the ability of LMM to assemble properly into filaments.
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• 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 14-23415176-A-G is Pathogenic according to our data. Variant chr14-23415176-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14123.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.5378T>C	p.Leu1793Pro	missense	Exon 37 of 40	NP_000248.2	P12883
	MYH7	NM_001407004.1		c.5378T>C	p.Leu1793Pro	missense	Exon 36 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.5378T>C	p.Leu1793Pro	missense	Exon 37 of 40	ENSP00000347507.3	P12883
	MYH7	ENST00000858540.1		c.5423T>C	p.Leu1808Pro	missense	Exon 37 of 40	ENSP00000528599.1
	MYH7	ENST00000965955.1		c.5423T>C	p.Leu1808Pro	missense	Exon 37 of 40	ENSP00000636014.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000429 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Hypertrophic cardiomyopathy (1)
1	-	-	Hypertrophic cardiomyopathy 1 (1)
1	-	-	Left ventricular noncompaction 5 (1)
1	-	-	Myosin storage myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.56		Gain of methylation at K1791 (P = 0.0494)
MVP		0.99
MPC		2.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		1.0
Mutation Taster		=0/100	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: rs121913654; hg19: chr14-23884385;