rs727504374

Variant names:

• chr14-23423947-A-C
• rs727504374
• NM_000257.4:c.2882T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-23423947-A-C
• chr14-23423947-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000257.4(MYH7):​c.2882T>G​(p.Leu961Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L961P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 9.13
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hypertrophic cardiomyopathy

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

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

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 14-23423947-A-C is Pathogenic according to our data. Variant chr14-23423947-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 264501.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.2882T>G	p.Leu961Arg	missense_variant	Exon 23 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.2882T>G	p.Leu961Arg	missense_variant	Exon 22 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.2882T>G	p.Leu961Arg	missense_variant	Exon 23 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.2882T>G	p.Leu961Arg	missense_variant	Exon 23 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.2882T>G	p.Leu961Arg	missense_variant	Exon 22 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 53412

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy 1 Pathogenic:1

Apr 15, 2025

Molecular Genetics Laboratory, Motol Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Detected in the mutational hot spot in exon 23 of the MYH7 gene (PM1). Rare variant with low frequency in gnomAD population databases (1x in non-Finnish European population) (PM2). In silico prediction tools support deleterious effect on the gene (PP3). Reputable source reports this variant as pathogenic (MYH7_000814, Leiden Open Variation Database v.3.0) (PP5). Strongly enriched in the submitter's cohort of patients with hypertrophic cardiomyopathy (ten unrelated individuals with HCM) (PS4). Cosegregation with disease in multiple affected family members with HCM (PP1). Therefore, this variant is classified as pathogenic. -

not specified Uncertain:1

Jun 09, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the MYH7 gene. The L961R variant has been previously reported in at least one individual diagnosed with HCM (Curila et al., 2012), although no segregation data are available. The L961R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L961R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals, and it lacks both segregation and functional studies which would further clarify its pathogenicity. Additionally, while missense variants at the same residue (L961P, L961V) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Bainbridge et al., 2015; Walsh et al., 2017), the clinical significance of these variants also remains to be definitively determined. Lastly, L961R is also classified as a variant of uncertain significance in ClinVar by a different clinical laboratory (ClinVar SCV000320482.1; Landrum et al., 2016). -

Hypertrophic cardiomyopathy Uncertain:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 961 of the MYH7 protein (p.Leu961Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22455086). ClinVar contains an entry for this variant (Variation ID: 264501). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Feb 20, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L961R variant (also known as c.2882T>G), located in coding exon 21 of the MYH7 gene, results from a T to G substitution at nucleotide position 2882. The leucine at codon 961 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in one individual reported to have hypertrophic cardiomyopathy (HCM) (Curila K, et al. Acta Cardiol 2012;67(1):23-9). Other alterations affecting the same amino acid, p.L961P (c.2882T>C) and p.L961V (c.2881C>G), have been reported in association with HCM (Bainbridge MN et al. Circ Cardiovasc Genet, 2015 Aug;8:544-52; Walsh R et al. Genet. Med. 2017;19:192-203).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
CardioboostCm	Uncertain	0.79
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.45	T
Polyphen		1.0	D
Vest4		0.97
MutPred		0.78		Loss of ubiquitination at K966 (P = 0.0506);
MVP		0.88
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		1.0
Mutation Taster		=4/96	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: rs727504374; hg19: chr14-23893156;