VCV000014065.49 - ClinVar

NM_000432.4(MYL2):c.64G>A (p.Glu22Lys)

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.

(23)

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/Likely 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_000432.4(MYL2):c.64G>A (p.Glu22Lys)

Variation ID: 14065 Accession: VCV000014065.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.11 12: 110919133 (GRCh38) [ NCBI UCSC ] 12: 111356937 (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	Apr 4, 2013	Oct 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000432.4:c.64G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000423.2:p.Glu22Lys	missense
NC_000012.12:g.110919133C>T
NC_000012.11:g.111356937C>T
NG_007554.1:g.6445G>A
NG_065206.1:g.281C>T
LRG_393:g.6445G>A
LRG_393t1:c.64G>A	LRG_393p1:p.Glu22Lys
	P10916:p.Glu22Lys

... more HGVS ... less HGVS

Protein change

E22K

Other names

p.E22K:GAA>AAA

Canonical SPDI

NC_000012.12:110919132:C:T

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

probably has functional consequence

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.

0.00020 (T)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA010513 Leiden Muscular Dystrophy (MYL2): MYL2_00003 UniProtKB: P10916#VAR_004603 OMIM: 160781.0002 dbSNP: rs104894368 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.
LOC114827850	-	-	-	GRCh38	-	129
MYL2		-	-	GRCh38 GRCh37	436	571

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.
Hypertrophic cardiomyopathy 10	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jan 20, 2024	RCV000015109.43
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Dec 13, 2022	RCV000158914.29
Death in early adulthood	Pathogenic (1)	no assertion criteria provided	Mar 27, 2015	RCV000234985.4
Hypertrophic cardiomyopathy	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000768488.13
Cardiomyopathy	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 21, 2023	RCV001170438.11
Cardiovascular phenotype	Likely pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV002354163.6
MYL2-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 25, 2023	RCV004532354.1

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 (Jul 28, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 10 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000744074.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 10 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745544.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Dec 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004026231.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PS4, PP3, PM2_SUP, PS3
Likely pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812326.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (6) PubMed: 11102452‚ 12668451‚ 14594949‚ 16076902‚ 17606808‚ 26497160 Comment: This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 … (more) This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,590 alleles) in the Latino/Admixed American population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio = 8.4, 95 % CI:1.64 to 43.5; VariantFX Cardiac Allele Frequencies, DECIPHER vs gnomAD v2.1 Latino/Admixed American population). The variant has been reported to segregate with cardiomyopathy across multiple affected families and is associated with incomplete penetrance and later onset of hypertrophic cardiomyopathy (PMID: 26497160). In vitro functional assays and transgenic mouse models showed a significant change in the calcium-binding properties for this variant indicating it impacts protein function (PMID: 11102452, 16076902, 17606808, 14594949, 12668451). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.714). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4_Moderate (less)
Likely pathogenic (Jul 15, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 10 Affected status: yes Allele origin: germline	Center for Medical Genetics Ghent, University of Ghent Accession: SCV000299269.1 First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016	Publications: PubMed (1) PubMed: 16076902
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Human Genetics, University of Leuven Accession: SCV000886792.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019
Pathogenic (Oct 18, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000927440.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
Pathogenic (Sep 24, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203862.4 First in ClinVar: Jan 31, 2015 Last updated: Jul 03, 2020	Publications: PubMed (14) PubMed: 21896538‚ 9724616‚ 26497160‚ 25324513‚ 14594949‚ 27532257‚ 8673105‚ 12404107‚ 11102452‚ 10948063‚ 12668451‚ 16751284‚ 16076902‚ 17606808 Comment: The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, … (more) The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, Walsh 2017, LMM data). This variant reportedly did not segregate with disease in several affected relatives, though at least 4 of these individuals were reported to have additional risk factors or carried additional variants in cardiomyopathy related genes (Alvarez-Acosta 2014, Claes 2015). This variant has also been identified in 5/251472 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and had been reported in ClinVar (Variation ID #14065). Multiple in vitro and transgenic animal studies have shown that the p.Glu22Lys variant impacts protein function (Levine 1998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2. (less) Number of individuals with the variant: 1
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501723.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (17) PubMed: 8673105‚ 26497160‚ 25324513‚ 33673806‚ 21310275‚ 12404107‚ 31513939‚ 12668451‚ 11102452‚ 17606808‚ 14594949‚ 33087929‚ 30847666‚ 32665702‚ 32880476‚ 27532257‚ 33548158 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Apr 04, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208849.10 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population … (more) Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E22K alters MYL2 function (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Roopnarine et al., 2003; Szczesna-Cordary et al., 2007, Farman et al., 2014; Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 16751284, 9724616, 31513939, 17606808, 12668451, 25324513, 8673105, 12404107, 21310275, 27532257, 28166811, 28138913, 27435932, 28606303, 26497160, 28790153, 16076902, 30605904, 21896538, 10948063, 30847666, 33673806, 32665702, 32880476, 33087929, 33662488, 11102452, 33548158) (less)
Likely pathogenic (Mar 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333018.3 First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (Apr 25, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYL2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117554.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see … (more) The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Poetter et al. 1996. PubMed ID: 8673105; Robyns et al. 2020. PubMed ID: 31513939; Walsh et al. 2017. PubMed ID: 27532257). Multiple functional studies suggest this variant alters protein function (see for example, Zhang et al. 2021. PubMed ID: 33548158; Szczesna-Cordary et al. 2007. PubMed ID: 17606808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-111356937-C-T). This variant is interpreted as pathogenic. (less)
Pathogenic (Jan 20, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy 10 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000549155.9 First in ClinVar: Sep 09, 2016 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 8673105‚ 12404107‚ 26497160‚ 27532257‚ 12668451‚ 14594949‚ 16076902‚ 17606808‚ 25324513 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein (p.Glu22Lys). This variant is present in population databases (rs104894368, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 12404107, 26497160, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14065). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYL2 function (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001351143.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 203862‚ 8673105‚ 12404107‚ 12668451‚ 14594949‚ 16076902‚ 17606808‚ 25324513‚ 26497160‚ 27532257 Comment: This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact … (more) This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy from over 20 families (PMID: 8673105, 12404107, 26497160, 27532257; ClinVar SCV000203862.4). This variant has shown reduced penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 carriers from 14 Dutch families has suggested that this variant together with the presence of an additional risk factor, such as hypertension, contributes to the development of hypertrophic cardiomyopathy (PMID: 26497160). This variant has been identified in 5/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004845869.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (9) PubMed: 8673105‚ 12404107‚ 12668451‚ 14594949‚ 16076902‚ 17606808‚ 25324513‚ 26497160‚ 27532257 Comment: The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported … (more) The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported in more than 40 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 12404107, 26497160, 27532257), and has been shown to segregate with HCM in several families (PMID: 27532257, 12404107). This variant has shown incomplete penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 heterozygous individuals from 14 Dutch families has suggested that this variant is a founder variant with shared haplotype in the Netherlands, and that the presence of an additional risk factor, such as hypertension, contributes to the development of HCM (PMID: 26497160). Functional studies have shown that this variant affects MYL2 protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.714). This variant has been identified in 5/251472 chromosomes in the general population (gnomAD). Based on these evidence, the c.64G>A (p.Glu22Lys) variant of the MYL2 gene is interpreted as pathogenic. (less) Number of individuals with the variant: 7
Likely pathogenic (Jul 25, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002655548.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (27) PubMed: 10948063‚ 11102452‚ 12404107‚ 12668451‚ 14594949‚ 16076902‚ 17606808‚ 21896538‚ 25324513‚ 25351510‚ 26497160‚ 27435932‚ 27532257‚ 28138913‚ 28166811‚ 28771489‚ 30706179‚ 30847666‚ 31513939‚ 32880476‚ 33548158‚ 33662488‚ 33673806‚ 35050212‚ 35653365‚ 8673105‚ 9724616 Comment: The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide … (more) The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele that presents with incomplete penetrance. (less)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002585422.15 First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024	Comment: MYL2: PP1:Strong, PM1, PM2, PS4:Moderate Number of individuals with the variant: 1
Pathogenic (Nov 01, 2002)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035366.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2018	Publications: PubMed (2) PubMed: 8673105‚ 12404107 Comment on evidence: In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on … (more) In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified heterozygosity for a glu22-to-lys (E22K) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. Kabaeva et al. (2002) identified the E22K mutation, resulting from a heterozygous 64G-A transition in the MYL2 gene, in 7 members (4 affected and 3 with 'uncertain' phenotypes) of a family with CMH10 who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918311.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953668.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Mar 27, 2015)	no assertion criteria provided Method: clinical testing	Death in early adulthood Affected status: yes Allele origin: unknown	Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences Study: HCIFS-Postmortem genetic screening project Accession: SCV000263119.1 First in ClinVar: Jul 15, 2016 Last updated: Jul 15, 2016	Publications: PubMed (4) PubMed: 27435932‚ 8673105‚ 11102452‚ 12668451 Clinical Features: Death in early adulthood (present) Age: 20-29 years Sex: male Ethnicity/Population group: Hispanic Americans Tissue: Blood
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Hypertrophic cardiomyopathy 10 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733135.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
not provided (Mar 26, 2012)	no classification provided Method: curation	Familial hypertrophic cardiomyopathy 10 Affected status: not provided Allele origin: germline	Leiden Muscular Dystrophy (MYL2) Accession: SCV000045755.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
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Comment:

This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,590 alleles) in the Latino/Admixed American population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio = 8.4, 95 % CI:1.64 to 43.5; VariantFX Cardiac Allele Frequencies, DECIPHER vs gnomAD v2.1 Latino/Admixed American population). The variant has been reported to segregate with cardiomyopathy across multiple affected families and is associated with incomplete penetrance and later onset of hypertrophic cardiomyopathy (PMID: 26497160). In vitro functional assays and transgenic mouse models showed a significant change in the calcium-binding properties for this variant indicating it impacts protein function (PMID: 11102452, 16076902, 17606808, 14594949, 12668451). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.714). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4_Moderate

Comment:

The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, Walsh 2017, LMM data). This variant reportedly did not segregate with disease in several affected relatives, though at least 4 of these individuals were reported to have additional risk factors or carried additional variants in cardiomyopathy related genes (Alvarez-Acosta 2014, Claes 2015). This variant has also been identified in 5/251472 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and had been reported in ClinVar (Variation ID #14065). Multiple in vitro and transgenic animal studies have shown that the p.Glu22Lys variant impacts protein function (Levine 1998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2.

Comment:

Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E22K alters MYL2 function (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Roopnarine et al., 2003; Szczesna-Cordary et al., 2007, Farman et al., 2014; Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 16751284, 9724616, 31513939, 17606808, 12668451, 25324513, 8673105, 12404107, 21310275, 27532257, 28166811, 28138913, 27435932, 28606303, 26497160, 28790153, 16076902, 30605904, 21896538, 10948063, 30847666, 33673806, 32665702, 32880476, 33087929, 33662488, 11102452, 33548158)

Comment:

The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Poetter et al. 1996. PubMed ID: 8673105; Robyns et al. 2020. PubMed ID: 31513939; Walsh et al. 2017. PubMed ID: 27532257). Multiple functional studies suggest this variant alters protein function (see for example, Zhang et al. 2021. PubMed ID: 33548158; Szczesna-Cordary et al. 2007. PubMed ID: 17606808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-111356937-C-T). This variant is interpreted as pathogenic.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein (p.Glu22Lys). This variant is present in population databases (rs104894368, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 12404107, 26497160, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14065). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYL2 function (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic.

Comment:

This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy from over 20 families (PMID: 8673105, 12404107, 26497160, 27532257; ClinVar SCV000203862.4). This variant has shown reduced penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 carriers from 14 Dutch families has suggested that this variant together with the presence of an additional risk factor, such as hypertension, contributes to the development of hypertrophic cardiomyopathy (PMID: 26497160). This variant has been identified in 5/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported in more than 40 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 12404107, 26497160, 27532257), and has been shown to segregate with HCM in several families (PMID: 27532257, 12404107). This variant has shown incomplete penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 heterozygous individuals from 14 Dutch families has suggested that this variant is a founder variant with shared haplotype in the Netherlands, and that the presence of an additional risk factor, such as hypertension, contributes to the development of HCM (PMID: 26497160). Functional studies have shown that this variant affects MYL2 protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.714). This variant has been identified in 5/251472 chromosomes in the general population (gnomAD). Based on these evidence, the c.64G>A (p.Glu22Lys) variant of the MYL2 gene is interpreted as pathogenic.

Comment:

The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele that presents with incomplete penetrance.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
probably has functional consequence			Leiden Muscular Dystrophy (MYL2) Accession: SCV000045755.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory.	Stava TT	European journal of preventive cardiology	2022	PMID: 35653365
Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management.	Pezzoli L	Journal of cardiovascular development and disease	2021	PMID: 35050212
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients.	Alimohamed MZ	International journal of cardiology	2021	PMID: 33662488
Hypertrophic cardiomyopathy associated E22K mutation in myosin regulatory light chain decreases calcium-activated tension and stiffness and reduces myofilament Ca(2+) sensitivity.	Zhang J	The FEBS journal	2021	PMID: 33548158
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Implications of Genetic Testing in Dilated Cardiomyopathy.	Verdonschot JAJ	Circulation. Genomic and precision medicine	2020	PMID: 32880476
Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time.	van Rooij J	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32665702
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains.	Yadav S	Pflugers Archiv : European journal of physiology	2019	PMID: 30706179
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.	Mademont-Soler I	PloS one	2017	PMID: 28771489
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.	Kobayashi Y	Genome medicine	2017	PMID: 28166811
Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data.	Alejandra Restrepo-Cordoba M	Journal of cardiovascular translational research	2017	PMID: 28138913
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young.	Methner DN	Genome research	2016	PMID: 27435932
Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers.	Claes GR	European heart journal	2016	PMID: 26497160
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy.	Lopes LR	Heart (British Cardiac Society)	2015	PMID: 25351510
Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics.	Farman GP	Journal of applied physiology (Bethesda, Md. : 1985)	2014	PMID: 25324513
Genetic basis of end-stage hypertrophic cardiomyopathy.	Garcia-Pavia P	European journal of heart failure	2011	PMID: 21896538
Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy.	Jordan DM	American journal of human genetics	2011	PMID: 21310275
Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients.	Szczesna-Cordary D	FASEB journal : official publication of the Federation of American Societies for Experimental Biology	2007	PMID: 17606808
E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics.	Dumka D	American journal of physiology. Heart and circulatory physiology	2006	PMID: 16751284
The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.	Szczesna-Cordary D	Journal of cell science	2005	PMID: 16076902
Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction.	Szczesna-Cordary D	The Journal of biological chemistry	2004	PMID: 14594949
Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy.	Roopnarine O	Biophysical journal	2003	PMID: 12668451
Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy.	Kabaeva ZT	European journal of human genetics : EJHG	2002	PMID: 12404107
Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation.	Szczesna D	The Journal of biological chemistry	2001	PMID: 11102452
In vivo analysis of an essential myosin light chain mutation linked to familial hypertrophic cardiomyopathy.	Sanbe A	Circulation research	2000	PMID: 10948063
Structural and functional responses of mammalian thick filaments to alterations in myosin regulatory light chains.	Levine RJ	Journal of structural biology	1998	PMID: 9724616
Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.	Poetter K	Nature genetics	1996	PMID: 8673105
Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli.	Hughes JM	Nature	1978	PMID: 203862
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Text-mined citations for rs104894368 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000432.4(MYL2):c.64G>A (p.Glu22Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894368 ...