12-110919133-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PP3PP5_Very_Strong

The NM_000432.4(MYL2):c.64G>A(p.Glu22Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

MYL2
NM_000432.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22O:1

Conservation

PhyloP100: 7.53

Variant links:

Genes affected

MYL2 (HGNC:7583): (myosin light chain 2) This gene encodes a major sarcomeric protein in mammalian striated muscle. The encoded protein plays a role in embryonic heart muscle structure and function, while phosphorylation of the encoded protein is involved in cardiac myosin cycling kinetics, torsion and function in adults. Mutations in this gene are associated with hypertrophic cardiomyopathy 10 and infant-onset myopathy. [provided by RefSeq, May 2022]

MYL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a chain Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (size 164) in uniprot entity MLRV_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000432.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

PP5

Variant 12-110919133-C-T is Pathogenic according to our data. Variant chr12-110919133-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110919133-C-T is described in Lovd as [Pathogenic]. Variant chr12-110919133-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 7	ENST00000228841.15	NP_000423.2	P10916Q6IB42
MYL2	NM_001406745.1 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 6		NP_001393674.1
MYL2	NM_001406916.1 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 2 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL2	ENST00000228841.15 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 7	1	NM_000432.4	ENSP00000228841.8	P10916
MYL2	ENST00000548438.1 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 6	3		ENSP00000447154.1	G3V1V8
MYL2	ENST00000663220.1 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 2 of 7			ENSP00000499568.1	A0A590UJU8
MYL2	ENST00000546404.1 link	c.64G>A	p.Glu22Lys	missense_variant	Exon 2 of 2	2		ENSP00000499645.1	A0A590UK07

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251472

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 03, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 13, 2022

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PP3, PM2_SUP, PS3 -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYL2: PP1:Strong, PM1, PM2, PS4:Moderate -

Apr 04, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Oct 18, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 10

Pathogenic:6Other:1

Nov 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2012

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Jul 15, 2016

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hypertrophic cardiomyopathy

Pathogenic:4

Oct 31, 2018

Center for Human Genetics, University of Leuven

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A transgenic mouse model has shown that this variant causes a phenotype consistent with hypertrophic cardiomyopathy, including decline in rigor tension and enhanced actin-activated myosin ATPase activity (PMID: 33548158). Additional 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, 33495596, 33495597, 33673806; 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. -

Sep 24, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Cardiomyopathy

Pathogenic:2

Mar 28, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

MYL2-related disorder

Pathogenic:1

Apr 25, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Cardiovascular phenotype

Pathogenic:1

Oct 04, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Death in early adulthood

Pathogenic:1

Mar 27, 2015

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

CardioboostCm

Uncertain

0.84

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.047

MutationAssessor

Benign

1.5

L;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.044

D;D

Polyphen

0.98

D;.

Vest4

0.89

MutPred

0.54

Gain of methylation at E22 (P = 0.0052);Gain of methylation at E22 (P = 0.0052);

MVP

0.90

MPC

0.79

ClinPred

0.91

GERP RS

4.4

Varity_R

0.92

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over