rs143139258

Variant names:

• chr12-110913097-T-G
• rs143139258
• NM_000432.4:c.401A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PP2 PP3_Strong BS1_Supporting

The NM_000432.4(MYL2):​c.401A>C​(p.Glu134Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000418 in 1,613,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 15/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E134D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: MYL2 NM_000432.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:14 O:1
• Conservation: PhyloP100: 7.64
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain EF-hand 3 (size 35) in uniprot entity MLRV_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_000432.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.39564 (below the threshold of 3.09). Trascript score misZ: 1.1124 (below the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy 10, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy, congenital fiber-type disproportion myopathy.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00027 (41/152002) while in subpopulation NFE AF = 0.000471 (32/67992). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000432.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	NM_000432.4	MANE Select	c.401A>C	p.Glu134Ala	missense splice_region	Exon 6 of 7	NP_000423.2
	MYL2	NM_001406745.1		c.359A>C	p.Glu120Ala	missense splice_region	Exon 5 of 6	NP_001393674.1
	MYL2	NM_001406916.1		c.344A>C	p.Glu115Ala	missense splice_region	Exon 6 of 7	NP_001393845.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYL2	ENST00000228841.15	TSL:1 MANE Select	c.401A>C	p.Glu134Ala	missense splice_region	Exon 6 of 7	ENSP00000228841.8
	MYL2	ENST00000713800.1		c.401A>C	p.Glu134Ala	missense splice_region	Exon 7 of 8	ENSP00000519106.1
	MYL2	ENST00000713803.1		c.401A>C	p.Glu134Ala	missense splice_region	Exon 7 of 8	ENSP00000519109.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000471

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000199 AC: 50 AN: 251490 AF XY: 0.000228

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000434 AC: 634 AN: 1461868 Hom.: 1 Cov.: 33 AF XY: 0.000435 AC XY: 316 AN XY: 727234

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000246 AC: 11 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000537 AC: 597 AN: 1111998

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152002 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74226

African (AFR) AF: 0.000121 AC: 5 AN: 41372

American (AMR) AF: 0.000262 AC: 4 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000415 Hom.: 0

Bravo AF: 0.000295

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:14 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Other:1

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant (p.Glu134Ala) is too common in gnomAD (v2.1.1 and v..4.1.0-non-UKB) to be classified as pathogenic. The clinical relevance of this observation is not clear. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898, 33495596, 33495597, 33732734). Therefore, pathogenicity of this variant is unclear today; hence, this variant is classified as a variant of unknown significance until more information becomes available.

Jan 20, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.401A>C affects a conserved nucleotide, resulting in amino acid change from Glu to Ala. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 19/121996 control chromosomes at a frequency of 0.0001557, predominantly observed in Latino and non-Finnish European subpopulations with MAF of 0.0003455 and 0.0002248 respectively in ExAC. The frequencies exceed the maximal expected frequency of a pathogenic allele (0.000075). This variant has been reported in multiple HCM pts and functional study showed that the actin binding in contraction is compromised by the E134A mutation (Burghardt_2013). An internal LCA sample carried this variant with co-occurrence of a pathogenic MYBPC3 variant (c.1504C>T, p.R502W). Via Clinivar, two clinical labs list variant with classification of likely pathogenic, one classified it as pathogenic, and another lab classified variant as VUS. Taking all evidence into consideration, although this variant has been reported in multiple affected individuals, it is also present at a relatively high frequency in the general population, and thus the pathogenicity of this variant is unclear at this moment; hence, this variant is classified as a variant of unknown significance until more information becomes available.

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3

Hypertrophic cardiomyopathy 10 Pathogenic:2 Uncertain:2

Feb 24, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 134 of the MYL2 protein (p.Glu134Ala). This variant is present in population databases (rs143139258, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20173211, 24111713, 25524337, 27483260, 27600940, 37652022). ClinVar contains an entry for this variant (Variation ID: 43475). 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: 23343568). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 18, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PM5,PP3,BS1

Hypertrophic cardiomyopathy Pathogenic:1 Uncertain:2

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Found in patient having exome sequencing for an unrelated indication. No known history of hypertrophic cardiomyopathy. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

Apr 05, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gnomad: 0.033 in NFE population, HGMD: Whiffin (2017) Genet Med 19: 1151 PubMed: 28518168 Additional literature report − classed as VUS. See Supplementary Table S1. (only additional report, refers Burghardt et al). %7C ClinVar: VUS by Invitae, Ambry, EGL , LP by University of Washington, Eric and Hanna Klessmann Institute. Reported in multiple individuals with cardiomyopathy but frequency higher than expected for a pathogenic variant. Conflicting information - VUS.

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with alanine at codon 134 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may impact RNA splicing. A functional study using a cardiac papillary muscle fiber system has shown that this variant reduces actin binding in contraction (PMID: 23343568). However, clinical relevance of this observation is not clear. This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898, 33495596, 33495597, 33732734). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 34935411, 35026164), and in one individual affected with respiratory syncytial virus-associated sudden death and an unaffected carrier parent (PMID: 31771554). This variant has been identified in 57/282826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Cardiomyopathy Uncertain:2

Jan 06, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with alanine at codon 134 of the MYL2 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may impact RNA splicing. A functional study using a cardiac papillary muscle fiber system has shown that this variant reduces actin binding in contraction (PMID: 23343568). This variant has been reported in at least six unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20173211, 23396983, 24111713, 31323898, 33495596, 33495597, 33732734). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 34935411, 35026164), and in one individual affected with respiratory syncytial virus-associated sudden death and an unaffected carrier parent (PMID: 31771554). However, this variant occurs at an elevated frequency in the general population and has been identified in 57/282826 chromosomes (45/129164 Non-Finnish European chromosomes at 0.0348%) by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Feb 24, 2020

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 10;C5561937:Myopathy, myofibrillar, 12, infantile-onset, with cardiomyopathy Uncertain:2

Mar 22, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Uncertain:2

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E134A variant (also known as c.401A>C), located in coding exon 6 of the MYL2 gene, results from an A to C substitution at nucleotide position 401. The glutamic acid at codon 134 is replaced by alanine, an amino acid with dissimilar properties. This variant has been reported in hypertrophic cardiomyopathy, dilated cardiomyopathy, and sudden cardiac arrest cohorts; however, in several cases clinical detail was limited, this variant was reported to co-occur with other cardiac-related genes, and/or this variant was also detected in unaffected family members (Olivotto I et al. Mayo Clin Proc. 2008;83:630-8; Di Donna P et al. Europace. 2010;12:347-55; Berge KE et al. Clin Genet. 2014;86:355-60; Cecconi M et al. Int J Mol Med. 2016;38(4):1111-24; Stpie-Wojno M et al. Pol Arch Intern Med. 2018;12; Mademont-Soler I et al. PLoS ONE. 2017;12(8):e0181465; Klauke B et al. PLoS One, 2017 Dec;12:e0189489;; Gavotto A et al. BMC Pediatr, 2019 11;19:462). This variant has also been detected in population-based cohorts and exome cohorts with unclear cardiovascular history (Bick AG. Am J Hum Genet. 2012;91(3):513-9; Andreasen C et al. Eur J Hum Genet. 2013;21:918-28; Dorschner MO et al. Am J Hum Genet. 2013 Oct;93:631-40). An in vitro study suggested that this alteration may reduce actin binding (Burghardt TP et al. Biochemistry. 2013;52:1249-59). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Apr 08, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dilated cardiomyopathy 1S Pathogenic:1

May 01, 2016

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Primary dilated cardiomyopathy Pathogenic:1

Sep 22, 2016

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.79	P
Vest4		0.93
MVP		0.97
MPC		1.0
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.88
gMVP		0.83
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		0.0
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143139258; hg19: chr12-111350901;