NM_000432.4:c.401A>C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 7P and 5B. PM1PP3_StrongPP5BS1_SupportingBS2

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. 14/24 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).

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:5U:14O:1

Conservation

PhyloP100: 7.64

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 Uncertain_significance. Variant got 2 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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 12-110913097-T-G is Pathogenic according to our data. Variant chr12-110913097-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43475.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=12, not_provided=1}. Variant chr12-110913097-T-G is described in Lovd as [Pathogenic].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYL2	NM_000432.4 link	c.401A>C	p.Glu134Ala	missense_variant, splice_region_variant	Exon 6 of 7	ENST00000228841.15	NP_000423.2	P10916Q6IB42
MYL2	NM_001406745.1 link	c.359A>C	p.Glu120Ala	missense_variant, splice_region_variant	Exon 5 of 6		NP_001393674.1
MYL2	NM_001406916.1 link	c.344A>C	p.Glu115Ala	missense_variant, splice_region_variant	Exon 6 of 7		NP_001393845.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYL2	ENST00000228841.15 link	c.401A>C	p.Glu134Ala	missense_variant, splice_region_variant	Exon 6 of 7	1	NM_000432.4	ENSP00000228841.8	P10916
MYL2	ENST00000548438.1 link	c.359A>C	p.Glu120Ala	missense_variant, splice_region_variant	Exon 5 of 6	3		ENSP00000447154.1	G3V1V8
MYL2	ENST00000663220.1 link	c.344A>C	p.Glu115Ala	missense_variant, splice_region_variant	Exon 6 of 7			ENSP00000499568.1	A0A590UJU8
MYL2	ENST00000549029.1 link	n.*36A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251490

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135920

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000435

AC XY:

316

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000537

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000270

AC:

AN:

152002

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000471

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Other:1

Leiden Muscular Dystrophy (MYL2)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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. -

Jun 01, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

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. -

Hypertrophic cardiomyopathy 10

Pathogenic:2Uncertain:2

Feb 24, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

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. -

Hypertrophic cardiomyopathy

Pathogenic:1Uncertain: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

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

- -

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. -

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

Uncertain:2

Jun 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostCm

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.79

P;.

Vest4

0.93

MVP

0.97

MPC

1.0

ClinPred

0.93

GERP RS

5.1

Varity_R

0.88

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

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

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