NM_000258.3(MYL3):c.427G>A (p.Glu143Lys) AND Hypertrophic cardiomyopathy

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 28, 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:: RCV000199993.16

Allele description

NM_000258.3(MYL3):c.427G>A (p.Glu143Lys)

Gene:

MYL3:myosin light chain 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.31

Genomic location:

Preferred name:

NM_000258.3(MYL3):c.427G>A (p.Glu143Lys)

Other names:

p.E143K:GAG>AAG

HGVS:

NC_000003.12:g.46859529C>T
NG_007555.2:g.27641G>A
NM_000258.3:c.427G>AMANE SELECT
NP_000249.1:p.Glu143Lys
NP_000249.1:p.Glu143Lys
LRG_395t1:c.427G>A
LRG_395:g.27641G>A
LRG_395p1:p.Glu143Lys
NC_000003.11:g.46901019C>T
NM_000258.2:c.427G>A
P08590:p.Glu143Lys
c.427G>A
p.(Glu143Lys)

Protein change:

E143K; GLU143LYS

Links:

Leiden Muscular Dystrophy (MYL3): MYL3_00009; UniProtKB: P08590#VAR_019843; OMIM: 160790.0003; dbSNP: rs104893750

NCBI 1000 Genomes Browser:

rs104893750

Molecular consequence:

NM_000258.3:c.427G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059674	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Aug 22, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 21823217, 22131351, 25910212, 25342278, 28658286, 27532257, 28371863, 12021217, 24033266
SCV000254448	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12021217, 21823217, 27532257, 22131351, 28492532
SCV001448933	Knight Diagnostic Laboratories, Oregon Health and Sciences University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 15, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059674

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Aug 22, 2019)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV000254448

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001448933

Knight Diagnostic Laboratories, Oregon Health and Sciences University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 15, 2019)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	17	13	not provided	not provided	not provided	clinical testing

Citations

PubMed

Widespread macromolecular interaction perturbations in human genetic disorders.

Sahni N, Yi S, Taipale M, Fuxman Bass JI, Coulombe-Huntington J, Yang F, Peng J, Weile J, Karras GI, Wang Y, Kovács IA, Kamburov A, Krykbaeva I, Lam MH, Tucker G, Khurana V, Sharma A, Liu YY, Yachie N, Zhong Q, Shen Y, Palagi A, et al.

Cell. 2015 Apr 23;161(3):647-660. doi: 10.1016/j.cell.2015.04.013.

PubMed [citation]

PMID:: 25910212
PMCID:: PMC4441215

Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing.

Gómez J, Reguero JR, Morís C, Martín M, Alvarez V, Alonso B, Iglesias S, Coto E.

Circ J. 2014;78(12):2963-71. Epub 2014 Oct 22.

PubMed [citation]

PMID:: 25342278

See all PubMed Citations (11)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059674.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	16	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Glu143Lys variant in MYL3 has been reported in the heterozygous state in >35 individuals with hypertrophic cardiomyopathy (HCM), many of whom are of reported Latino ancestry, suggesting it may be a founder mutation in that population (Gomez 2014, McNamara 2017, LMM data, GeneDx pers. comm., Invitae pers. comm., Ambry pers. comm.). A few of these individuals also carried a likely pathogenic variant in another HCM-associated gene. This variant has also been identified in the homozygous state in at least 5 individuals with early onset HCM or restrictive cardiomyopathy (RCM) and in 3 affected siblings who also had early onset disease (Olson 2002, Caleshu 2011, LMM data, Ambry pers. comm., Invitae pers comm.). Relatives who were heterozygous carriers of this variant were clinically unaffected (Olson, 2002, Caleshu 2011) suggesting reduced penetrance. Additionally, it has been reported by other clinical laboratories in ClinVar (Variant ID: 14063) and has been identified in 0.01% (4/35436) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vitro and in vivo functional studies, including transgenic mice expressing the p.Glu413Lys human variant that had clinical features of RCM, support an impact on protein function (Lossie 2012, Sahni 2015, Yuan 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for HCM with reduced penetrance and is associated a more severe presentation when a pathogenic variant is also found on the second copy of the gene. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		16	not provided	13	not provided

From Invitae, SCV000254448.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 143 of the MYL3 protein (p.Glu143Lys). This variant is present in population databases (rs104893750, gnomAD 0.009%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy and/or autosomal recessive restrictive cardiomyopathy (PMID: 12021217, 21823217, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14063). 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 MYL3 function (PMID: 22131351). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV001448933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Mar 10, 2024

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