14-23418397-C-T

Variant names:

• chr14-23418397-C-T
• rs372727092
• NM_000257.4:c.3982G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_000257.4(MYH7):​c.3982G>A​(p.Ala1328Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000286 in 1,606,482 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 7.69
• Publications: 5 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.

• 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, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3982G>A	p.Ala1328Thr	missense_variant	Exon 30 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3982G>A	p.Ala1328Thr	missense_variant	Exon 29 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3982G>A	p.Ala1328Thr	missense_variant	Exon 30 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.3982G>A	p.Ala1328Thr	missense_variant	Exon 30 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.3982G>A	p.Ala1328Thr	missense_variant	Exon 29 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 247162 AF XY: 0.0000149

Gnomad AFR exome AF: 0.0000632

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1454172 Hom.: 0 Cov.: 32 AF XY: 0.0000208 AC XY: 15 AN XY: 722174

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.000247 AC: 11 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5666

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1106796

Other (OTH) AF: 0.0000500 AC: 3 AN: 60006

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.00111 AC: 17 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:3

Jan 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Jun 20, 2013

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg238His (R238H; c.713 G>A) in the MYBPC3 gene Based on the data reviewed below, we consider this a variant of unknown significance (VUS). Variants with this classification are not suitable for predictive testing of family members, and they require more investigation. This variant has been reported previously in 2 unrelated cases of DCM, with difficult-to-interpret segregation data available from one family (Waldmiller et al. 2011, Supplementary Data; Pugh et al. 2014-Supplementary Data from Laboratory for Molecular Medicine). Waldmiller et al. found it in a Caucasian patient with DCM recruited in Germany. This is a conservative amino acid change from a positively-charged arginine to a positively-charged histidine, although the side-chains are very different in shape. The arginine at codon 238 is highly conserved (100% across 9 vertebrate species) as are the amino acids on either side. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Missense variants at nearby residues have been listed in HGMD in association with cardiomyopathy, supporting the functional importance of this region of the protein. In particular, 3 different amino acid variants at the adjacent codon 237 have been seen in association with cardiomyopathy: Asp228Asn, Ser236Gly, Tyr237Cys, Tyr237His, Tyr237Ser, Glu240Asp, Ser242Pro (HGMD professional version as of January 17, 2014). In total the variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is no variant at codon 238 listed in dbSNP or 1000 genomes (as of March 18, 2014).

Mar 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.3982G>A (p.Ala1328Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 247162 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3982G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy or Hypertrophic Cardiomyopathy (Pugh_2014, Walsh_2017, Goel_2018, Park_2022, Kurzlechner_2022, McGurk_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30511546, 35629155, 37652022, 34542152, 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 42985). Based on the evidence outlined above, the variant was classified as uncertain significance.

Cardiomyopathy Uncertain:2

Sep 16, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 1328 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 27532257, 35470680). This variant has also been reported in an individual affected with hypertrophic cardiomyopathy and in two asymptomatic family members of the family (PMID: 30511546). This variant has been identified in 6/278552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Mar 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces alanine with threonine at codon 1328 of the MYH7 protein. Computational prediction tools indicate that this variant's impact on protein structure and function is inconclusive. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 27532257, 35470680). This variant has also been reported in one individual affected with hypertrophic cardiomyopathy and in two asymptomatic family members (PMID: 30511546). This variant has been identified in 6/278552 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

not provided Uncertain:2

Aug 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 30511546, 37652022, 34542152, 24503780)

Oct 08, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1

Sep 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Uncertain:1

Dec 23, 2024

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 threonine, which is neutral and polar, at codon 1328 of the MYH7 protein (p.Ala1328Thr). This variant is present in population databases (rs372727092, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 24503780, 27532257, 30511546, 37652022). ClinVar contains an entry for this variant (Variation ID: 42985). 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

Apr 04, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3982G>A (p.A1328T) alteration is located in exon 30 (coding exon 28) of the MYH7 gene. This alteration results from a G to A substitution at nucleotide position 3982, causing the alanine (A) at amino acid position 1328 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
CardioboostCm	Benign	0.057
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.014	D
Sift4G	Benign	0.18	T
Vest4		0.88
ClinPred		0.67	D
GERP RS		5.0
Varity_R		0.27
gMVP		0.63
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372727092; hg19: chr14-23887606;