14-23419950-G-C

Variant names:

• chr14-23419950-G-C
• rs529700838
• NM_000257.4:c.3621C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP2 PP3_Moderate PP5

The NM_000257.4(MYH7):​c.3621C>G​(p.Ile1207Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,457,512 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. I1207N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: -2.25
• Publications: 3 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 19 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 14-23419950-G-C is Pathogenic according to our data. Variant chr14-23419950-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418363.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.3621C>G	p.Ile1207Met	missense_variant	Exon 27 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.3621C>G	p.Ile1207Met	missense_variant	Exon 26 of 39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3621C>G	p.Ile1207Met	missense_variant	Exon 27 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.3621C>G	p.Ile1207Met	missense_variant	Exon 27 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.3621C>G	p.Ile1207Met	missense_variant	Exon 26 of 39			ENSP00000519071.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1457512 Hom.: 0 Cov.: 35 AF XY: 0.0000179 AC XY: 13 AN XY: 724814

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5032

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1108844

Other (OTH) AF: 0.00 AC: 0 AN: 60190

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Sep 14, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I1207M likely pathogenic variant in the MYH7 gene has been previously reported in an individual with HCM progressing to heart failure and requiring a heart transplant, and was not detected in 800 control alleles (Melacini et al., 2010). The I1209M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant occurs at a position that is conserved across species and in silico predictions this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (E1205K, D1208N, N1209S, Q1215H) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al, 2014), supporting the functional importance of this region of the protein. However, the I1207M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Uncertain:1

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1207 of the MYH7 protein (p.Ile1207Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20513729, 33019804). ClinVar contains an entry for this variant (Variation ID: 418363). Advanced 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 at Invitae 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. -

Cardiovascular phenotype Uncertain:1

Sep 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1207M variant (also known as c.3621C>G), located in coding exon 25 of the MYH7 gene, results from a C to G substitution at nucleotide position 3621. The isoleucine at codon 1207 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in in an individual with hypertrophic cardiomyopathy (HCM) progressing to heart failure and transplant, and has also been detected in an individual from a dilated cardiomyopathy cohort; however, details were limited (Melacini P et al. Eur. Heart J., 2010 Sep;31:2111-23; Hey TM et al. Circ Heart Fail. 2020 10;13(10):e006701). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

MYH7-related disorder Uncertain:1

Aug 05, 2021

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MYH7 c.3621C>G (p.Ile1207Met) variant is a missense variant that has been reported in a heterozygous state in one individual with non-obstructive hypertrophic cardiomyopathy with preserved systolic function and atrial fibrillation who required a heart transplant at age 60 years (Melacini et al. 2010). This variant is not reported in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, suggesting it is rare. In silico algorithms are not consistent in their predictions of the functional effects of this variant. Based on the evidence, the p.Ile1207Met variant is classified as a variant of uncertain significance for MYH7-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.021	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-2.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.63
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.038	D
Polyphen		0.93	P
Vest4		0.70
MutPred		0.52		Gain of MoRF binding (P = 0.0854);
MVP		0.84
MPC		3.4
ClinPred		0.80	D
GERP RS		-1.6
Varity_R		0.28
gMVP		0.85
Mutation Taster		=44/56	disease causing (ClinVar)

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: rs529700838; hg19: chr14-23889159;