rs121913648

Variant names:

• chr14-23416104-ATCT-A
• rs121913648
• NM_000257.4:c.4850_4852delAGA

Your query was ambiguous. Multiple possible variants found:

• chr14-23416104-ATCT-A
• chr14-23416104-ATCT-ATCTTCT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.57
• Publications: 16 publications found

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]

MHRT (HGNC:51291): (myosin heavy chain associated RNA transcript) This gene encodes a spliced long non-coding RNA that may act as a cardioprotective agent in the heart. Based on a study of a similar gene in mouse, the encoded transcript may regulate chromatin remodeling by acting as a decoy to the BRG1 chromatin repressor complex thus preventing it from binding to its genomic targets. Blocking the actions of BRG1 could be crucial in protecting the heart from pathological hypertrophy. [provided by RefSeq, Dec 2014]

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000257.4
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 190401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4850_4852delAGA	p.Lys1617del	disruptive_inframe_deletion	Exon 34 of 40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.4850_4852delAGA	p.Lys1617del	disruptive_inframe_deletion	Exon 33 of 39		NP_001393933.1
MHRT	NR_126491.1	n.374_376delTTC		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4850_4852delAGA	p.Lys1617del	disruptive_inframe_deletion	Exon 34 of 40	1	NM_000257.4	ENSP00000347507.3
MYH7	ENST00000713768.1	c.4850_4852delAGA	p.Lys1617del	disruptive_inframe_deletion	Exon 34 of 41			ENSP00000519070.1
MYH7	ENST00000713769.1	c.4850_4852delAGA	p.Lys1617del	disruptive_inframe_deletion	Exon 33 of 39			ENSP00000519071.1

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:3 Other:1

Jan 01, 2013

Neurogenetics Laboratory, Royal Perth Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Most common recurrent pathogenic variant -

Oct 18, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

May 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-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) -

Nov 17, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 190401). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 20, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913648; hg19: chr14-23885313;