rs727504844

Positions:

• chr14-23415676-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000257.4(MYH7):​c.5110C>T​(p.Gln1704Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,718 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 Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 NM_000257.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.48

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5110C>T	p.Gln1704Ter	stop_gained	35/40	ENST00000355349.4	NP_000248.2
MHRT	NR_126491.1	n.108G>A		non_coding_transcript_exon_variant	2/6
MYH7	NM_001407004.1	c.5110C>T	p.Gln1704Ter	stop_gained	34/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5110C>T	p.Gln1704Ter	stop_gained	35/40	1	NM_000257.4	ENSP00000347507	P1
	ENST00000557368.1	n.197G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461718 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2013

Variant classified as Uncertain Significance - Favor Pathogenic. The Gln1704X va riant in MYH7 has not been reported in individuals with cardiomyopathy or in lar ge European American and African American populations (NHLBI exome sequencing pr oject). This nonsense variant leads to a premature termination codon at position 1704, which is predicted to lead to a truncated or absent protein. It should be noted that loss of function variants in the MYH7 gene are very rare and therefo re, their phenotypic spectrum is unknown. In the few reported cases with MYH7 no nsense variants, all were present in trans along with another MYH7 variant in a severely affected, young individual and in all cases the nonsense variant was in herited from an unaffected parent, suggesting that heterozygous loss of function of MYH7 may not be disease causing (Houghs 2005, Nishi 1995, LMM unpublished da ta). In summary, although this variant severely impacts the protein, additional studies are needed to fully assess its clinical significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2017

p.Gln1704Stop (CAG>TAG): c.5110 C>T in exon 35 of the MYH7 gene (NM_000257.2). The Gln1704Stop variant in the MYH7 gene has not been reported as a disease-causing mutation or as benign polymorphism to our knowledge. Gln1704Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Although nonsense mutations in the MYH7 gene have been reported in association with cardiomyopathy, the vast majority of mutations in MYH7 are missense changes. Furthermore, various studies have conflicting hypotheses regarding MYH7 haploinsufficiency leading to cardiomyopathy (Nishi H et al., 1995; Waldmuller S et al., 2011). With the clinical and molecular information available at this time, we cannot definitively determine if Gln1704Stop is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.85
GERP RS		5.4

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: rs727504844; hg19: chr14-23884885;