14-23415475-ATCT-A

Position:

• chr14-23415475-ATCT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000257.4(MYH7):​c.5186_5188delAGA​(p.Lys1729del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH7 NM_000257.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 5.78

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 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 14-23415475-ATCT-A is Pathogenic according to our data. Variant chr14-23415475-ATCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 42096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-23415475-ATCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5186_5188delAGA	p.Lys1729del	disruptive_inframe_deletion	36/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5186_5188delAGA	p.Lys1729del	disruptive_inframe_deletion	35/39		NP_001393933.1
MHRT	NR_126491.1	n.36_38delTCT		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5186_5188delAGA	p.Lys1729del	disruptive_inframe_deletion	36/40	1	NM_000257.4	ENSP00000347507.3
ENSG00000258444	ENST00000557368.1	n.126+21_126+23delTCT		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461888 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 02, 2020	The p.Lys1729del variant has been reported in multiple individuals with Laing distal myopathy and has been shown to segregate with disease in >10 affected family members from at least 3 families (Hedera 2003 PMID:12975303, Meredith 2004 PMID:15322983, Muelas 2010 PMID:20733148, Muelas 2012 PMID:21395566, Roda 2014 PMID:25574480, Petri 2019 PMID:30874888). It is considered to be a founder variant in individuals from the Safor region of Spain (Muelas 2012 PMID:21395566). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 42096) and was absent from large population studies. The p.Lys1729del variant has not been reported in individuals with isolated cardiomyopathy; however, a range of cardiac phenotypes, including dilated cardiomyopathy, were noted in some affected individuals with myopathy (Hedera 2003 PMID:12975303, Muelas 2010 PMID:20733148, Roda 2014 PMID:25574480). Typically, small deletions and amino acid changes to proline located in the 3' end of MYH7 (exons 34-36) have been associated with Laing distal myopathy (Meredith 2004) whereas variants in other domains of the protein are causative of hypertrophic (HCM) and dilated cardiomyopathies (DCM); however, about one third of patients with Laing myopathy develop HCM or DCM (Lamont and Laing, 2015, GeneReviews). This variant is a deletion of 1 amino acid at position 1729 and is not predicted to alter the protein reading-frame. Functional studies in Drosophila support an impact on protein function as it was shown that this variant results in abnormal muscle structure and function (Dahl-Halverson 2018 PMID: 29946036). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Laing distal myopathy, but there is insufficient evidence to determine if the phenotypic spectrum also includes cardiomyopathy or other cardiac phenotypes. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2, PS3_Moderate, PM4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 15322983, 20733148, 21395566, 25574480). It has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 25574480). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000042096). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2012	- -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This variant, c.5186_5188del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Lys1729del), 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 individual(s) with Laing distal myopathy in several large families and is considered a founder mutation among individuals of Mediterranean ancestry (PMID: 12975303, 15322983, 20733148, 21395566, 25574480). It is commonly reported in individuals of Mediterranean ancestry (PMID: 12975303, 15322983, 20733148, 21395566, 25574480). ClinVar contains an entry for this variant (Variation ID: 42096). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2020

The c.5186_5188delAGA variant (also known as p.K1729del) is located in coding exon 34 of the MYH7 gene. This variant results from an in-frame AGA deletion at nucleotide positions 5186 to 5188. This results in the in-frame deletion of a lysine at codon 1729. This variant has been reported to be a Mediterranean founder mutation (Muelas N et al. Clin. Genet., 2012 May;81:491-4). In addition, this variant has been detected in multiple individuals and segregates with Laing distal myopathy in multiple unrelated families (Muelas N et al. Clin. Genet., 2012 May;81:491-4; Muelas N et al. Neurology, 2010 Aug;75:732-41; Hedera P et al. Arch. Neurol., 2003 Sep;60:1321-5; Roda RH et al. Ann Clin Transl Neurol, 2014 Dec;1:1053-8; Meredith C et al. Am. J. Hum. Genet., 2004 Oct;75:703-8). This variant has also been detected in a family with variable cardiac findings (Petri H et al. J. Neurol., 2019 Jun;266:1367-1375). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Congenital myopathy with fiber type disproportion Other:1

not provided, no classification provided

literature only

GeneReviews

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367543052; hg19: chr14-23884684;