14-23414007-C-T

Variant names:

• chr14-23414007-C-T
• rs753392652
• NM_000257.4:c.5655G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3 PP5

The NM_000257.4(MYH7):​c.5655G>A​(p.Ala1885Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MYH7 NM_000257.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• Conservation: PhyloP100: -0.134
• Publications: 9 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.

• 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 14-23414007-C-T is Pathogenic according to our data. Variant chr14-23414007-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 378215.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5655G>A	p.Ala1885Ala	splice_region_variant, synonymous_variant	Exon 38 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5655G>A	p.Ala1885Ala	splice_region_variant, synonymous_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.5655G>A	p.Ala1885Ala	splice_region_variant, synonymous_variant	Exon 38 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.5655G>A	p.Ala1885Ala	splice_region_variant, synonymous_variant	Exon 38 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.5655G>A	p.Ala1885Ala	splice_region_variant, synonymous_variant	Exon 37 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000119 AC: 3 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727214

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

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

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

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

Alfa AF: 0.0000534 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Pathogenic:2 Uncertain:2

Apr 19, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant alters the conserved c.G at the last nucleotide of exon 38 of the MYH7 gene and has been shown to cause aberrant splicing and in-frame skipping of exon 38 (p.1854_1885del) (PMID: 26782017, 27387980, 30794915). This variant is expected to result in the expression of a shortened protein missing a part of LMM domain, which is a C-terminal tail region that forms the thick filament backbone and interacts with other proteins (PMID: 25125180). This variant has been reported in two individuals affected with congenital myopathy without cardiac involvement (PMID: 26782017, 33333461) and in one individual affected with congenital myopathy with cardiac left bundle block (PMID: 27387980), and has been reported to occur de novo in two of these affected individuals (PMID: 26782017, 27387980). This variant has not been reported in individuals affected with hypertrophic cardiomyopathy. It has been observed in three asymptomatic older adults (PMID: 34135346). This variant has been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant may have adverse structural impact by disrupting RNA splicing, but its impact on MYH7 protein function remains unknown. While this variant has been observed in individuals with congenital myopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant hypertrophic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jan 07, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MYH7 c.5655G>A (p.Ala1885Ala) alters a conserved nucleotide, specifically, the last nucleotide of exon 38, adjacent to the canonical exon 38 / intron 38 splice donor site, which could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. Multiple publications reports experimental evidence that this variant affects mRNA splicing, resulting in exon 38 skipping, confirmed by minigene assay and cDNA sequencing (e.g. Pajusalu_2016, Fiorillo_2016, Surikova_2019). The variant allele was found at a frequency of 1.2e-05 in 251438 control chromosomes. c.5655G>A has been reported in the literature as a de novo occurrence in individuals affected with early onset of muscular weakness and delayed motor development in infancy or congenital axial and distal lower limb weakness, severe scoliosis, and left bundle block (e.g. Pajusalu_2016, Fiorillo_2016). The variant has also been reported without confirmed causality, in additional individuals affected with cardiomyopathy, delayed motor development, muscle weakness, hypertrophic cardiomyopathy, coronary artery disease, or in asymptomatic individuals (e.g. Abdulrahim_2021, Zhu_2020, Natera-deBenito_2021, Murdock_2021, Bourfiss_2022, Lacaze_2021). Together, these data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32792077, 36264615, 27387980, 34135346, 34363016, 33333461, 26782017, 30794915, 33240318). ClinVar contains an entry for this variant (Variation ID: 378215). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 17, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This synonymous variant alters the conserved c.G at the last nucleotide of exon 38 of the MYH7 gene and has been shown to cause aberrant splicing and in-frame skipping of exon 38 (p.1854_1885del) (PMID: 26782017, 27387980, 30794915). This variant is expected to result in the expression of a shortened protein missing a part of LMM domain, which is a C-terminal tail region that forms the thick filament backbone and interacts with other proteins (PMID: 25125180). This variant has been reported in two individuals affected with congenital myopathy without cardiac involvement (PMID: 26782017, 33333461) and in one individual affected with congenital myopathy with cardiac left bundle block (PMID: 27387980). This variant has been reported as a de novo occurrence in two affected individuals (PMID: 26782017, 27387980). This variant has not been reported in individuals affected with hypertrophic cardiomyopathy. It has been observed in three asymptomatic older adults (PMID: 34135346). This variant has been identified in 3/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant may have adverse structural impact by disrupting RNA splicing, but its impact on MYH7 protein function remains unknown. While this variant has been observed in individuals with congenital myopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant hypertrophic cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hypertrophic cardiomyopathy 1 Pathogenic:2

Jan 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5655G>A (p.Ala1885=) in the MYH7 gene is a synonymous variant located in last nucleotide of exon 38, which is part of the consensus splice site for this exon. Experimental studies have shown that this variant affects proper mRNA splicing, resulting in an in-frame skipping of exon 38 and a shortening of the encoded protein by 32 amino acids (PMID: 26782017, 27387980). This variant has been reported in two individuals: one with early onset muscular weakness and fiber-type disproportion (PMID: 26782017) and a second patient with an early infantile onset of respiratory muscle impairment and left bundle branch block (PMID: 27387980). Notably, several patients with different genomic variants but identical exon 38 skipping (c.5655+1G>A, c.5655+5G>C) also demonstrate cardiac manifestations in the form of dilated cardiomyopathy and left ventricular non-compaction (PMID: 30794915, 27387980). This variant has been observed at an ultra-low frequency in the general population (gnomAD database 3/251,438). For these reasons, this variant has been classified as Likely Pathogenic. -

Dilated cardiomyopathy 1S Pathogenic:1

Jan 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MYH7-related skeletal myopathy Pathogenic:1

Jan 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myosin storage myopathy Pathogenic:1

Jan 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 21, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); RNA studies demonstrate a damaging effect through in-frame skipping of exon 38 (PMID: 27387980, 26782017, 30794915); This variant is associated with the following publications: (PMID: 30794915, 27387980, 26782017, 33240318, 34135346, 34363016, Li_2024_Article, 33333461, 36264615) -

Myopathy, myosin storage, autosomal recessive Pathogenic:1

Jan 31, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 1885 of the MYH7 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYH7 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs753392652, gnomAD 0.003%). This variant has been observed in individual(s) with MYH7-related myopathy (PMID: 26782017, 27387980). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 378215). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of skipping of exon 38, but is expected to preserve the integrity of the reading-frame (PMID: 26782017, 27387980). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 16, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5655G>A pathogenic mutation (also known as p.A1885A), located in coding exon 36 of the MYH7 gene, results from a G to A substitution at nucleotide position 5655. This nucleotide substitution does not change the alanine at codon 1885. However, this change occurs in the last base pair of coding exon 36, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in multiple individuals with MYH7-related myopathies and reportedly arose de novo in three of the cases (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91; Invitae pers. comm.; GeneDx pers. comm.; Ambry internal data). RNA studies indicate that this variant disrupts normal splicing, leading to the in-frame skipping of exon 38 (Pajusalu S et al. Neuromuscul. Disord., 2016 Mar;26:236-9; Fiorillo C et al. Orphanet J Rare Dis, 2016 07;11:91). Internal structural assessment suggests that the predicted resulting in-frame deletion would disrupt the coiled-coil formation in the Assembly Competency Domain, which appears to be critical for thick filament assembly (Sohn RL et al. J. Mol. Biol., 1997 Feb;266:317-30; Delorenzi M et al. Bioinformatics, 2002 Apr;18:617-25; Gruber M et al. J. Struct. Biol., 2006 Aug;155:140-5; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation for MYH7-related skeletal myopathy; however, the association with cardiomyopathy is unclear. -

MYH7-related disorder Pathogenic:1

Jan 16, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM2, PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.83
PhyloP100		-0.13
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
Splicevardb		3.0
SpliceAI score (max)		0.030		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: rs753392652; hg19: chr14-23883216; COSMIC: COSV62518931; COSMIC: COSV62518931;