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

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Feb 5, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000768488.11

Allele description

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

Genes:
LOC114827850:VISTA enhancer hs2149 [Gene]
MYL2:myosin light chain 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q24.11
Genomic location:
Preferred name:
NM_000432.4(MYL2):c.64G>A (p.Glu22Lys)
Other names:
p.E22K:GAA>AAA
HGVS:
  • NC_000012.12:g.110919133C>T
  • NG_007554.1:g.6445G>A
  • NG_065206.1:g.281C>T
  • NM_000432.4:c.64G>AMANE SELECT
  • NP_000423.2:p.Glu22Lys
  • NP_000423.2:p.Glu22Lys
  • LRG_393t1:c.64G>A
  • LRG_393:g.6445G>A
  • LRG_393p1:p.Glu22Lys
  • NC_000012.11:g.111356937C>T
  • NM_000432.3:c.64G>A
  • P10916:p.Glu22Lys
  • p.(Glu22Lys)
Protein change:
E22K; GLU22LYS
Links:
Leiden Muscular Dystrophy (MYL2): MYL2_00003; UniProtKB: P10916#VAR_004603; OMIM: 160781.0002; dbSNP: rs104894368
NCBI 1000 Genomes Browser:
rs104894368
Molecular consequence:
  • NM_000432.4:c.64G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
probably has functional consequence
Observations:
3

Condition(s)

Name:
Hypertrophic cardiomyopathy
Synonyms:
HYPERTROPHIC MYOCARDIOPATHY
Identifiers:
MONDO: MONDO:0005045; MeSH: D002312; MedGen: C0007194; Human Phenotype Ontology: HP:0001639

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000203862Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Pathogenic
(Sep 24, 2019)
germlineclinical testing

PubMed (15)
[See all records that cite these PMIDs]

SCV000886792Center for Human Genetics, University of Leuven
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Oct 31, 2018)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004812326Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Jul 7, 2023)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004845869All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 5, 2024)
germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown81not provided108544not providedclinical testing
not providedgermlineyesnot provided2not providednot providednot providedclinical testing

Citations

PubMed

Genetic basis of end-stage hypertrophic cardiomyopathy.

Garcia-Pavia P, Vázquez ME, Segovia J, Salas C, Avellana P, Gómez-Bueno M, Vilches C, Gallardo ME, Garesse R, Molano J, Bornstein B, Alonso-Pulpon L.

Eur J Heart Fail. 2011 Nov;13(11):1193-201. doi: 10.1093/eurjhf/hfr110. Epub 2011 Sep 6.

PubMed [citation]
PMID:
21896538

Structural and functional responses of mammalian thick filaments to alterations in myosin regulatory light chains.

Levine RJ, Yang Z, Epstein ND, Fananapazir L, Stull JT, Sweeney HL.

J Struct Biol. 1998;122(1-2):149-61.

PubMed [citation]
PMID:
9724616
See all PubMed Citations (16)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000203862.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (15)

Description

The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Álvarez-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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

From Center for Human Genetics, University of Leuven, SCV000886792.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot provided2not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV004812326.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

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

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004845869.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided7not providednot providedclinical testing PubMed (10)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided7not providednot providednot provided

Last Updated: May 1, 2024