rs121913653

chr14-23429040-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 7P and 12B. PM1 PP2 PP3_Strong BP6_Very_Strong BS1

The NM_000257.4(MYH7):c.1322C>T(p.Thr441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,082 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 Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T441T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:2 B:8
• Conservation: PhyloP100: 0.776

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000257.4
• PP2: Missense variant where missense usually causes diseases, MYH7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• BP6: Variant 14-23429040-G-A is Benign according to our data. Variant chr14-23429040-G-A is described in ClinVar as [Benign]. Clinvar id is 14122.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr14-23429040-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000664 (97/1461894) while in subpopulation EAS AF= 0.00128 (51/39700). AF 95% confidence interval is 0.001. There are 0 homozygotes in gnomad4_exome. There are 49 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH7	NM_000257.4	c.1322C>T	p.Thr441Met	missense_variant	14/40	ENST00000355349.4
MYH7	NM_001407004.1	c.1322C>T	p.Thr441Met	missense_variant	13/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.1322C>T	p.Thr441Met	missense_variant	14/40	1	NM_000257.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251494 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00256

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.0000674 AC XY: 49 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00128

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000706 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Cardiomyopathy Benign:4

Benign, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Jun 16, 2021	The c.1322C>T (p.Thr441Met) in MYH7 has been identified in 0.2% (FAF 95% CI; 47/18394) of East Asian chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be classified as benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1, PM1. -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jan 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 03, 2018	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2016	The T441M variant in the MYH7 gene has been reported previously in one child with skeletal myopathy with mild atrial enlargement and septal thickness in the 95th percentile and was absent in 200 control chromosomes (Darin et al., 2007). Expression studies showed that mutated and wild-type alleles were equally expressed at the mRNA level (Darin et al., 2007). The T441M variant has also been reported in one Chinese family with hypertrophic cardiomyopathy (Fan et al., 2011; Feng et al., 2011). The T441M variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The T441M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position in the myosin motor domain that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (N437D, M439T, M439R, V440M, R442C, R442H, I443T, N444S) 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. We interpret T441M as a variant of uncertain significance, which may be related to the muscle weakness and atrophy reported in this individual. -

MYH7-related skeletal myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 05, 2007

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 30, 2017

MYH7 1322C>T: Disclaimer: This variant has not undergone a full assessment. The following are preliminary notes: Classified as VUS3 in 2014 and no new pubs sin ce then. Has a max MAF in ExAC of 0.15% (13 alleles) and gnomad of 0.27% (53 al leles) - frequency too high for disease. -

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

- -

Hypertrophic cardiomyopathy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
CardioboostCm	Uncertain	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.99	L
MutationTaster	Benign	1.2e-8	A
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.029	D
Sift4G	Benign	0.17	T
Polyphen		0.0040	B
Vest4		0.73
MutPred		0.75		Gain of catalytic residue at T441 (P = 0.0011);
MVP		0.89
MPC		1.2
ClinPred		0.027	T
GERP RS		2.3
Varity_R		0.048
gMVP		0.79

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: rs121913653; hg19: chr14-23898249;