rs727504844

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

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

Scores

5
1
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.48
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 UniProt
MYH7NM_000257.4 linkuse as main transcriptc.5110C>T p.Gln1704Ter stop_gained 35/40 ENST00000355349.4
MHRTNR_126491.1 linkuse as main transcriptn.108G>A non_coding_transcript_exon_variant 2/6
MYH7NM_001407004.1 linkuse as main transcriptc.5110C>T p.Gln1704Ter stop_gained 34/39

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.5110C>T p.Gln1704Ter stop_gained 35/401 NM_000257.4 P1
ENST00000557368.1 linkuse as main transcriptn.197G>A non_coding_transcript_exon_variant 2/23

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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 27, 2013Variant 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 submitterclinical testingGeneDxJan 08, 2017p.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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727504844; hg19: chr14-23884885; API