chr14-23419950-G-C

Position:

• chr14-23419950-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. 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).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH7. . Gene score misZ 3.9329 (greater than the threshold 3.09). Trascript score misZ 6.7889 (greater than threshold 3.09). GenCC has associacion of gene with hyaline body myopathy, MYH7-related skeletal myopathy, dilated cardiomyopathy 1S, congenital myopathy 7A, myosin storage, autosomal dominant, dilated cardiomyopathy, left ventricular noncompaction, myopathy, myosin storage, autosomal dominant, hypertrophic cardiomyopathy, congenital heart disease, Ebstein anomaly, arrhythmogenic right ventricular cardiomyopathy, myopathy, myosin storage, autosomal recessive, hypertrophic cardiomyopathy 1, familial isolated dilated 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 id is 418363.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.3621C>G	p.Ile1207Met	missense_variant	27/40	1	NM_000257.4	ENSP00000347507.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2015

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 418363). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20513729, 33019804). This variant is not present in population databases (gnomAD no frequency). 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). -

MYH7-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 05, 2021

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2022

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. -

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
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs529700838; hg19: chr14-23889159;