NM_000257.4:c.5561C>T

Variant names:

• chr14-23414101-G-A
• rs372381770
• NM_000257.4:c.5561C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3 PP5

The NM_000257.4(MYH7):​c.5561C>T​(p.Thr1854Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. T1854K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense, splice_region
• Scores: Splicing: ADA: 0.9737
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8
• Conservation: PhyloP100: 7.97
• Publications: 17 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: Uncertain_significance. The variant received 3 ACMG points.

• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 14-23414101-G-A is Pathogenic according to our data. Variant chr14-23414101-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161320.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5561C>T	p.Thr1854Met	missense_variant, splice_region_variant	Exon 38 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5561C>T	p.Thr1854Met	missense_variant, splice_region_variant	Exon 37 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5561C>T	p.Thr1854Met	missense_variant, splice_region_variant	Exon 38 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5561C>T	p.Thr1854Met	missense_variant, splice_region_variant	Exon 38 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5561C>T	p.Thr1854Met	missense_variant, splice_region_variant	Exon 37 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249812 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1459772 Hom.: 0 Cov.: 33 AF XY: 0.0000344 AC XY: 25 AN XY: 726264

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

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

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51440

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

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111890

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000596 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Feb 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 23299917, 27532257, 15358028, 25086479, 23283745, 31638223, 31737537, 22267749) -

Jun 12, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Pathogenic:1 Uncertain:1

Jul 20, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with methionine at codon 1854 in the LMM domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 25086479, 27532257, 23283745, 31110529, 31638223, 33495597, 34912951, 37121957, 38757491; communication with an external laboratory; ClinVar SCV000546198.5). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 37461109) and in an individual affected with ischemic stroke (PMID: 36973604). This variant has been identified in 8/281196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1854 of the MYH7 protein (p.Thr1854Met). This variant is present in population databases (rs372381770, gnomAD 0.006%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 15358028, 23283745, 25086479, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 161320). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Mar 29, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1854Met variant in MYH7 has been reported in >8 individuals with HCM and segregated with HCM in 1 affected relative (Van Dreist 2004 PMID: 15358028; reported incorrectly as p.Thr1834Met, Zou 2013 PMID: 23283745, Chiou 2015 PMID: 25086479, Walsh 2017 PMID: 27532257, Wang 2019 PMID: 31638223, Bonaventura 2019 PMID: 31110529, LMM data, Bristol genetics laboratory pers. comm.). This variant was also identified, along with a pathogenic variant in another HCM disease causing gene, in 1 individual and their affected realtive (Page 2012 PMID: 22267749). This variant was also reported by other clinical laboratories in ClinVar (Variation ID 161320) and has also been identified in 0.0065% (1/15286) Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Thr1854Met variant is uncertain. ACMG/AMP Criteria applied: PS4_Moderate, PM2_Supporting, PP3. -

Cardiovascular phenotype Pathogenic:1 Uncertain:1

Apr 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1854M variant (also known as c.5561C>T), located in coding exon 36 of the MYH7 gene, results from a C to T substitution at nucleotide position 5561. The threonine at codon 1854 is replaced by methionine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Aug;44:602-10 (reported as T1834M); Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Walsh R et al. Genet. Med., 2017 02;19:192-203), and has been reported to co-occur with variants in other cardiomyopathy-related genes in individuals with HCM (Page SP et al. Circ Cardiovasc Genet, 2012 Apr;5:156-66; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dec 28, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PP3 -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hypertrophic cardiomyopathy 1 Uncertain:1

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established; however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous; however, a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 8 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated myosin tail 1 domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Thr1854Lys) variant has been classified once as a VUS (LOVD). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified multiple times as a VUS by clinical diagnostic laboratories (ClinVar). However, this variant has also been identified in at least 15 unrelated individuals with hypertophic cardiomyopathy and/or septal hypertrophy (three individuals from Atlas of Cardiac Genetic Variation, at least nine individuals from Invitae (personal communication) and five individuals from the literature (PMIDs: 15358028, 23283745, 31638223)). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostCm	Uncertain	0.68
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.98
MPC		1.5
ClinPred		0.57	D
GERP RS		5.1
Varity_R		0.28
gMVP		0.91
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.79
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: rs372381770; hg19: chr14-23883310; COSMIC: COSV62519640; COSMIC: COSV62519640;