rs727503245

Variant names:

• chr14-23418255-T-C
• rs727503245
• NM_000257.4:c.4124A>G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000257.4(MYH7):​c.4124A>G​(p.Tyr1375Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.74

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]

MIR208B (HGNC:33669): (microRNA 208b) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 64) in uniprot entity MYH7_HUMAN there are 16 pathogenic changes around while only 1 benign (94%) in NM_000257.4
• PM2: Very rare variant in population databases, with high coverage
• 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 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, 0.951
• PP5: Variant 14-23418255-T-C is Pathogenic according to our data. Variant chr14-23418255-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164293.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2, Pathogenic=1}. Variant chr14-23418255-T-C is described in Lovd as [Pathogenic]. Variant chr14-23418255-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4124A>G	p.Tyr1375Cys	missense_variant	Exon 30 of 40	ENST00000355349.4	NP_000248.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4124A>G	p.Tyr1375Cys	missense_variant	Exon 30 of 40	1	NM_000257.4	ENSP00000347507.3
MIR208B	ENST00000401172.1	n.-192A>G		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1375 of the MYH7 protein (p.Tyr1375Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 28790153, 32894683). ClinVar contains an entry for this variant (Variation ID: 164293). 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) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr1375 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27247418, 33407484). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Apr 01, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr1375Cys variant in MYH7 has been identified in 3 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 5 affected relatives from 1 family (Burns 2017, Walsh 2017, LMM data). It was also reported in ClinVar (Variation ID 164293) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Tyr1375Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4_Supporting, PM2, PP1_Moderate, PP3. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Jan 22, 2019

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The MYH7 Tyr1375Cys variant is absent from the large Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools Mutation taster, SIFT, Polyphen-2 and PolyPhen-HCM are all supportive of a deleterious role. This variant has been previously identified in several HCM probands (Alfares AA, et al., 2015; Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, Pers. Comm.; Walsh R, et al., 2017) and was found to segregate in 4 affected family members in one family (LMM, Pers. Comm.). We identified this variant in a 51yo male with HCM (IVS = 30mm), and the variant was found to segregate in one affected family member (Ingles J, et al., 2017). Interestingly, a different rare variant at this position (Tyr1375His) has also been reported in HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant is, rare in the general population (PM2), segregates in at least 2 families (PP1_Moderate), has been identified in multiple cases (PS4_supporting) and in silico tools predict it to deleterious (PP3), therefore we classify MYH7 Tyr1375Cys as 'likely pathogenic'. -

Cardiomyopathy Uncertain:1

Mar 25, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Jan 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y1375C variant (also known as c.4124A>G), located in coding exon 28 of the MYH7 gene, results from an A to G substitution at nucleotide position 4124. The tyrosine at codon 1375 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ho CY et al. Circulation, 2018 Oct;138:1387-1398; Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465; Luo Q et al. Sci Rep, 2020 Jan;10:349; Mattivi CL et al. Circ Genom Precis Med, 2020 Oct;13:453-459). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.95
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.97
MutPred		0.61		Gain of methylation at K1374 (P = 0.0294);
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.80
gMVP		0.99

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: rs727503245; hg19: chr14-23887464;