rs397516220

Positions:

• chr14-23416987-TCTC-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000355349.4(MYH7):​c.4522_4524del​(p.Glu1508del) variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1508E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYH7 ENST00000355349.4 inframe_deletion, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 7.71

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000355349.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 14-23416987-TCTC-T is Pathogenic according to our data. Variant chr14-23416987-TCTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43023.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=6, Uncertain_significance=1}. Variant chr14-23416987-TCTC-T is described in Lovd as [Pathogenic]. Variant chr14-23416987-TCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.4522_4524del	p.Glu1508del	inframe_deletion, splice_region_variant	33/40	ENST00000355349.4	NP_000248.2
MHRT	NR_126491.1	n.634_636del		non_coding_transcript_exon_variant	4/6
MYH7	NM_001407004.1	c.4522_4524del	p.Glu1508del	inframe_deletion, splice_region_variant	32/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.4522_4524del	p.Glu1508del	inframe_deletion, splice_region_variant	33/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727246

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.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MYH7-related skeletal myopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	Jan 01, 2022	The c.4522_4524del (p.Glu1508del) MYH7 variant has been reported in our laboratory in a 50-year-old patient with diagnosis of distal myopathy and dilated cardiomyopathy with inconclusive muscle biopsy and MR. A 19-year-old son with a similar disorder from 4-year-old and another asymptomatic 14-year-old (not studied). Father died of sudden death at age 50 with an asymptomatic mother. This variant has been previously reported in a patients with myopathy and cardiomyopathy [PMID 15322983, 19477645, 21279644, 24664454, 24710723, 25695922, 26094647, 28403181]. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 43023). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function but to date there are no functional/experimental studies. In summary, c.4522_4524del (p.Glu1508del) MYH7 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity and having been widely described in relation to the patient´s phenotype. -
Pathogenic, no assertion criteria provided	clinical testing	Neurogenetics Laboratory, Royal Perth Hospital	Jan 01, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2013	proposed classification - variant undergoing re-assessment, contact laboratory -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2015	The c.4522_4524delGAG variant in the MYH7 gene has been reported previously in several multigenerationfamilies with Laing distal myopathy, including two affected individuals without a familyhistory of myopathy (Dubourg et al., 2011; Van den Bergh et al., 2014; Lamont et al., 2014; Naddaf etal., 2015; Reis et al., 2015). Some individuals also had co-morbid dilated cardiomyopathy (Dubourg etal., 2011; Lamont et al., 2014; Naddaf et al., 2015). The c.4522_4524delGAG variant causes anin-frame deletion of codon Glutamic acid 1508, denoted p.E1508del. The c.4522_4524delGAGvariant occurs within a coiled coil region of the protein that is conserved across species. Furthermore,this in-frame deletion was not observed in approximately 6500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. Therefore, we interpret c.4522_4524delGAG as a pathogenic variant -

Congenital myopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PM1+PM2+PM4+PP4+PP3+PP5 -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This variant, c.4522_4524del, results in the deletion of 1 amino acid(s) of the MYH7 protein (p.Glu1508del), 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, and distal myopathy associated with cardiomyopathy (PMID: 21279644, 24664454, 24710723, 25695922, 26094647). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43023). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2022

The c.4522_4524delGAG pathogenic mutation (also known as p.E1508del) is located in coding exon 31 of the MYH7 gene. This pathogenic mutation results from an in-frame GAG deletion at nucleotide positions 4522 to 4524. This results in the in-frame deletion of a glutamic acid at codon 1508. This alteration has been reported in multiple individuals with concerns for skeletal myopathy and segregated with disease in two different families (Dubourg O et al. J. Neurol., 2011 Jun;258:1157-63; Lamont PJ et al. Hum Mutat, 2014 Jul;35:868-79; Van den Bergh PY et al. Acta Neurol Belg, 2014 Dec;114:253-6; Naddaf E et al. J Clin Neuromuscul Dis, 2015 Mar;16:164-9; Reis GF et al. Neuropathology, 2015 Dec;35:575-81; Yu M et al. PLoS One, 2017 May;12:e0175343). Additionally, this alteration was found to be de novo in an individual with Laing myopathy (Dubourg O et al. J. Neurol., 2011 Jun;258:1157-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This variant causes an in-frame deletion of glutamic acid at codon 1508 in the is located in the LMM domain of the MYH7 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 individuals and families affected with Liang distal myopathy (PMID: 19477645, 21279644, 24664454, 24710723, 25695922, 26094647, 32833721, 33298082). Among these individuals affected with Liang distal myopathy, several were also affected with dilated cardiomyopathy (PMID: 24664454, 25695922, 32833721). It has been shown that this variant segregates with disease in multiple affected individuals across multiple families (PMID: 21279644, 25695922, 32833721). This variant has been reported as a de novo occurrence in at least two individuals affected with Liang distal myopathy (PMID: 21279644, 24710723). It has also been reported in one family with multiple individuals affected with distal hereditary motor neuropathy (PMID: 36539320). This variant has been reported in two unrelated individuals affected with dilated cardiomyopathy (PMID: 20474083). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Cardiac involvement is rarely observed in Liang distal myopathy (PMID: 33298082). Although this variant is pathogenic for Laing distal myopathy, the available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs397516220; hg19: chr14-23886196;