rs797044596

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong

The NM_000257.4(MYH7):​c.4850_4852delAGA​(p.Lys1617del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

MYH7
NM_000257.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.57
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 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000257.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 14-23416104-ATCT-A is Pathogenic according to our data. Variant chr14-23416104-ATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23416104-ATCT-A is described in Lovd as [Pathogenic]. Variant chr14-23416104-ATCT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYH7NM_000257.4 linkuse as main transcriptc.4850_4852delAGA p.Lys1617del disruptive_inframe_deletion 34/40 ENST00000355349.4 NP_000248.2 P12883
MYH7NM_001407004.1 linkuse as main transcriptc.4850_4852delAGA p.Lys1617del disruptive_inframe_deletion 33/39 NP_001393933.1
MHRTNR_126491.1 linkuse as main transcriptn.374_376delTTC non_coding_transcript_exon_variant 3/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYH7ENST00000355349.4 linkuse as main transcriptc.4850_4852delAGA p.Lys1617del disruptive_inframe_deletion 34/401 NM_000257.4 ENSP00000347507.3 P12883

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:3Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 2004- -
not provided, no classification providedliterature onlyGeneReviews-Most common recurrent pathogenic variant -
Pathogenic, no assertion criteria providedclinical testingNeurogenetics Laboratory, Royal Perth HospitalJan 01, 2013- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenOct 18, 2017- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 19, 2024In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27081534, 24664454, 24300783, 15322983, 27387980, 29660325, 31130284, 32833721, 25214167, 33298082, 31069529) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 17, 2023- -
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 23, 2022For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 190401). This variant has been observed in individuals with autosomal dominant early-onset Laing distal myopathy (PMID: 15322983, 16103042, 24300783, 24664454, 27387980). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.4850_4852del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Lys1617del), but otherwise preserves the integrity of the reading frame. -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsAug 20, 2024The c.4850_4852delAGA variant (also known as p.K1617del) is located in coding exon 32 of the MYH7 gene. This variant results from an in-frame AGA deletion at nucleotide positions 4850 to 4852. This results in the in-frame deletion of a lysine at codon 1617. This variant was reported in multiple individuals with features consistent with skeletal myopathy myopathy, and segregated with disease in families. One individual with skeletal myopathy was also reported to have dilated cardiomyopathy (Meredith C. et al. Am. J. Hum. Genet. 2004 Oct;75(4):703-8; Lamont PJ et al. Hum Mutat. 2014 Jul;35(7):868-79; Komlósi K et al. Neuromuscul Disord. 2014 Feb;24(2):156-61; Oda T et al. Hum Genome Var, 2015 Jul;2:15022; Savarese M et al. Acta Neuropathol Commun. 2014 Sep;2:100; Monies D et al. Am J Hum Genet, 2019 Jun;104:1182-1201; Ganapathy A et al. J Neurol, 2019 Aug;266:1919-1926; Lee HH et al. Genet Test Mol Biomarkers, 2020 Feb;24:99-104; Yu M et al. Orphanet J Rare Dis, 2020 Dec;15:344). One functional study indicated this variant may impair myofilament formation (Parker F et al. J Mol Biol, 2018 May;430:1459-1478). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic for MYH7-related skeletal myopathy; however, its clinical significance for MYH7-related cardiomyopathy is uncertain. -
Abnormality of the musculature Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingKariminejad - Najmabadi Pathology & Genetics CenterJul 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs121913648; hg19: chr14-23885313; API