rs121913648

chr14-23416104-ATCT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4_Supporting PP3 PP5_Very_Strong

The NM_000257.4(MYH7):c.4850_4852del(p.Lys1617del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYH7 NM_000257.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.57

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:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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, 14 uncertain in NM_000257.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000257.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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	UniProt
MYH7	NM_000257.4	c.4850_4852del	p.Lys1617del	inframe_deletion	34/40	ENST00000355349.4
MHRT	NR_126491.1	n.374_376del		non_coding_transcript_exon_variant	3/6
MYH7	NM_001407004.1	c.4850_4852del	p.Lys1617del	inframe_deletion	33/39

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH7	ENST00000355349.4	c.4850_4852del	p.Lys1617del	inframe_deletion	34/40	1	NM_000257.4	P1

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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Most common recurrent pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 18, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Neurogenetics Laboratory, Royal Perth Hospital	Jan 01, 2013	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	The c.4850_4852delAGA variant has been reported previously in association with Laing distal myopathy and other MYH7-related disorders (Meredith et al., 2004; Komlósi et al., 2014; Lamont et al., 2014; Oda et al., 2015; Fiorilloet al., 2016). The c.4850_4852delAGA variant results in an in-frame deletion of 1 amino acid residue, denoted p.Lys1617del. This variant is not observed in large population cohorts (Lek et al., 2016). Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Furthermore,in-frame deletions have been reported in the Human Gene Mutation Database in association with MYH7-related disorders (Stenson et al., 2014). Therefore, the c.4850_4852delAGA variant is considered a pathogenic variant and its presence is consistent with the diagnosis of an MYH7-related disorder in this individual. -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2022

For 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. -

Abnormality of the musculature Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs121913648; hg19: chr14-23885313;