rs121913644

Variant names:

• chr14-23425798-G-A
• rs121913644
• NM_000257.4:c.2183C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP6

The NM_000257.4(MYH7):​c.2183C>T​(p.Ala728Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,978 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A728A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 1.15
• Publications: 10 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 2 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000257.4
• 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.
• BP6: Variant 14-23425798-G-A is Benign according to our data. Variant chr14-23425798-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 14111.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	NM_000257.4	MANE Select	c.2183C>T	p.Ala728Val	missense	Exon 20 of 40	NP_000248.2
	MYH7	NM_001407004.1		c.2183C>T	p.Ala728Val	missense	Exon 19 of 39	NP_001393933.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH7	ENST00000355349.4	TSL:1 MANE Select	c.2183C>T	p.Ala728Val	missense	Exon 20 of 40	ENSP00000347507.3
	MYH7	ENST00000713768.1		c.2183C>T	p.Ala728Val	missense	Exon 20 of 41	ENSP00000519070.1
	MYH7	ENST00000713769.1		c.2183C>T	p.Ala728Val	missense	Exon 19 of 39	ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251186 AF XY: 0.000169

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 202 AN: 1461666 Hom.: 1 Cov.: 33 AF XY: 0.000136 AC XY: 99 AN XY: 727142

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000209 AC: 7 AN: 33472

American (AMR) AF: 0.000335 AC: 15 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86250

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000127 AC: 141 AN: 1111846

Other (OTH) AF: 0.000232 AC: 14 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74490

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Mar 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11424919, 30297972, 28518168, 27532257, 27247418, 23820649, 25935763, 27161882, 25637381, 23299917, 24055113)

Mar 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2183C>T; p.Ala728Val variant (rs121913644, ClinVar variant ID 14111) was detected and segregated with disease in a family affected with hypertrophic cardiomyopathy; however, another variant in this gene was located on the same chromosome, and was later determined to be clearly pathogenic (Blair 2001, Whiffin 2017), suggesting that the p.Ala728Val variant did not contribute to the disease. This variant is listed in the genome Aggregation Database (gnomAD) with a Latino population frequency of 0.04% (identified on 13 out of 34,420 chromosomes). The alanine at position 728 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Ala728Val variant on protein structure and function make conflicting predictions (SIFT: damaging, PolyPhen-2: benign). Based on the available information, the p.Ala728Val variant is likely to be benign.

Oct 12, 2022

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH7 c.2183C>T (p.Ala728Val) missense variant results in the substitution of alanine at amino acid 728 with valine. The c.2183C>T variant that has been reported in one study, in which it was found in a heterozygous state in two individuals from a single family with hypertrophic cardiomyopathy (PMID: 11424919). Both individuals also carried a second known pathogenic missense variant in cis. The variant is reported at a frequency of 0.000395 in the Latino population of the Genome Aggregation Database. Based on the available evidence, the c.2183C>T (p.Ala728Val) variant is classified as a variant of unknown significance for hypertrophic cardiomyopathy.

Cardiomyopathy Uncertain:1 Benign:1

Dec 31, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 18, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Jan 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Hypertrophic cardiomyopathy Uncertain:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 728 of the MYH7 protein (p.Ala728Val). This variant is present in population databases (rs121913644, gnomAD 0.04%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11424919). ClinVar contains an entry for this variant (Variation ID: 14111). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH7 protein function. 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.

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

Cardiovascular phenotype Benign:1

Mar 26, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Benign	0.060
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	1.3	L
PhyloP100		1.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.011	D
Sift4G	Benign	0.072	T
Polyphen		0.0050	B
Vest4		0.83
MVP		0.91
MPC		1.0
ClinPred		0.052	T
GERP RS		4.9
Varity_R		0.25
gMVP		0.88
Mutation Taster		=17/83	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: rs121913644; hg19: chr14-23895007; COSMIC: COSV62522014;