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

dbSNP: rs367543052

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035952	SCV000059604	pathogenic	MYH7-related skeletal myopathy	2020-09-02	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628918	SCV000749826	pathogenic	Hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	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.
Centogene AG - the Rare Disease Company	RCV000035952	SCV001426516	pathogenic	MYH7-related skeletal myopathy		criteria provided, single submitter	clinical testing
3billion	RCV000035952	SCV002318861	pathogenic	MYH7-related skeletal myopathy	2022-03-22	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002336112	SCV002643210	pathogenic	Cardiovascular phenotype	2020-07-20	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000035952	SCV000035448	pathogenic	MYH7-related skeletal myopathy	2012-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000034922	SCV000058529	not provided	Congenital myopathy with fiber type disproportion		no assertion provided	literature only