VCV000042096.20 - ClinVar

NM_000257.4(MYH7):c.5177AGA[3] (p.Lys1729del)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000257.4(MYH7):c.5177AGA[3] (p.Lys1729del)

Variation ID: 42096 Accession: VCV000042096.20

Type and length

Microsatellite, 3 bp

Location

Cytogenetic: 14q11.2 14: 23415476-23415478 (GRCh38) [ NCBI UCSC ] 14: 23884685-23884687 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 3, 2013	May 1, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000257.4:c.5177AGA[3] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000248.2:p.Lys1729del	inframe deletion
NM_000257.4:c.5186_5188del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000257.4:c.5186_5188delAGA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000257.3:c.5186_5188del
NR_126491.1:n.27TCT[3]		non-coding transcript variant
NC_000014.9:g.23415476TCT[3]
NC_000014.8:g.23884685TCT[3]
NG_007884.1:g.25175AGA[3]
LRG_384:g.25175AGA[3]
LRG_384t1:c.5186_5188del	LRG_384p1:p.Lys1729del

... more HGVS ... less HGVS

Protein change

K1729del

Other names

Canonical SPDI

NC_000014.9:23415475:TCTTCTTCTTCT:TCTTCTTCT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA015751 OMIM: 160760.0044 dbSNP: rs367543052 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYH7		No evidence available	No evidence available	GRCh38 GRCh37	3637	4914
LOC126861897	-	-	-	GRCh38	-	531
MHRT		-	-	GRCh38	-	785

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital myopathy with fiber type disproportion	not provided (1)	no classification provided	-	RCV000034922.11
MYH7-related skeletal myopathy	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 22, 2022	RCV000035952.20
Hypertrophic cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2023	RCV000628918.13
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jul 20, 2020	RCV002336112.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Sep 02, 2020)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	MYH7-related skeletal myopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059604.5 First in ClinVar: May 03, 2013 Last updated: May 29, 2021	Publications: PubMed (6) PubMed: 15322983‚ 12975303‚ 20733148‚ 21395566‚ 25574480‚ 30874888 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYH7-related skeletal myopathy Affected status: yes Allele origin: germline	3billion Accession: SCV002318861.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (4) PubMed: 21395566‚ 15322983‚ 25574480‚ 20733148 Comment: 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 … (more) 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. (less) Clinical Features: Myopathy (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYH7-related skeletal myopathy Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426516.1 First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020	Publications: PubMed (1) PubMed: 32860008
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000749826.4 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 12975303‚ 15322983‚ 20733148‚ 21395566‚ 25574480 Comment: 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. … (more) 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. (less)
Pathogenic (Jul 20, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002643210.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 12975303‚ 15322983‚ 20733148‚ 21395566‚ 25574480‚ 30874888 Comment: 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 … (more) 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. (less)
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	LAING DISTAL MYOPATHY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035448.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 10, 2016	Publications: PubMed (4) PubMed: 12975303‚ 15322983‚ 20733148‚ 21395566 Comment on evidence: In affected members of an Italian American family with Laing distal myopathy (MPD1; 160500) reported by Hedera et al. (2003), Meredith et al. (2004) identified … (more) In affected members of an Italian American family with Laing distal myopathy (MPD1; 160500) reported by Hedera et al. (2003), Meredith et al. (2004) identified a heterozygous 3-bp deletion of 1 of 3 consecutive AAG triplets in exon 36 of the MYH7 gene, resulting in the deletion of lys1729 (lys1729del). Muelas et al. (2010) identified the lys1729del mutation in 29 clearly affected individuals from 4 unrelated families in the Safor region of Spain. There was great phenotypic variability. The age at onset ranged from congenital to 50 years, with a mean of 14 years. All patients presented with weakness of great toe/ankle dorsiflexors, and many had associated neck flexor (78%), finger extensor (78%), mild facial (70%), or proximal muscle (65%) weakness. Five patients had cardiac abnormalities, including dilated cardiomyopathy, left ventricular relaxation impairment, and conduction abnormalities. The spectrum of disability ranged from asymptomatic to wheelchair-confined, but life expectancy was not affected. EMG showed myopathic and neurogenic features, and muscle biopsies showed fiber type disproportion, core/minicore lesions, and mitochondrial abnormalities. These findings expanded the phenotypic spectrum of Laing myopathy, but the wide spectrum associated with a single mutation was noteworthy. Muelas et al. (2012) identified a common 41.2-kb short haplotype including the lys1729del mutation in both Spanish patients from the Safor region and in the Italian American family reported by Hedera et al. (2003), indicating a founder effect. However, microsatellite markers both up- and downstream of the mutation did not match, indicating multiple recombination events. The mutation was estimated to have been introduced into the Safor population about 375 to 420 years ago (15 generations ago). The region is located in the southeast of Valencia on the Mediterranean coast of Spain. Muelas et al. (2012) hypothesized that the families from Safor were descendants of the Genoese who had repopulated this Spanish region in the 17th century after the Muslims were expelled; in fact, many of the surnames of the Safor families with Laing myopathy had an Italian origin. (less)
not provided (-)	no classification provided Method: literature only	Congenital myopathy with fiber type disproportion Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000058529.2 First in ClinVar: May 03, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20733148‚ 20301436 BookShelf: NBK1259 BookShelf: NBK1259

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.	Bertoli-Avella AM	European journal of human genetics : EJHG	2021	PMID: 32860008
Congenital myopathies are mainly associated with a mild cardiac phenotype.	Petri H	Journal of neurology	2019	PMID: 30874888
Laing distal myopathy pathologically resembling inclusion body myositis.	Roda RH	Annals of clinical and translational neurology	2014	PMID: 25574480
Congenital Fiber-Type Disproportion – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.	Adam MP	-	2013	PMID: 20301436
Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients.	Muelas N	Clinical genetics	2012	PMID: 21395566
MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy.	Muelas N	Neurology	2010	PMID: 20733148
Mutations in the slow skeletal muscle fiber myosin heavy chain gene (MYH7) cause laing early-onset distal myopathy (MPD1).	Meredith C	American journal of human genetics	2004	PMID: 15322983
The second kindred with autosomal dominant distal myopathy linked to chromosome 14q: genetic and clinical analysis.	Hedera P	Archives of neurology	2003	PMID: 12975303

Text-mined citations for rs367543052 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000257.4(MYH7):c.5177AGA[3] (p.Lys1729del)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs367543052 ...