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NM_000258.3(MYL3):c.170C>G (p.Ala57Gly) AND Hypertrophic cardiomyopathy

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Jan 22, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000229595.13

Allele description [Variation Report for NM_000258.3(MYL3):c.170C>G (p.Ala57Gly)]

NM_000258.3(MYL3):c.170C>G (p.Ala57Gly)

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.170C>G (p.Ala57Gly)
Other names:
p.A57G:GCC>GGC
HGVS:
  • NC_000003.12:g.46860813G>C
  • NG_007555.2:g.26357C>G
  • NM_000258.3:c.170C>GMANE SELECT
  • NP_000249.1:p.Ala57Gly
  • NP_000249.1:p.Ala57Gly
  • LRG_395t1:c.170C>G
  • LRG_395:g.26357C>G
  • LRG_395p1:p.Ala57Gly
  • NC_000003.11:g.46902303G>C
  • NM_000258.2:c.170C>G
  • p.(Ala57Gly)
Protein change:
A57G
Links:
Leiden Muscular Dystrophy (MYL3): MYL3_00008; dbSNP: rs139794067
NCBI 1000 Genomes Browser:
rs139794067
Molecular consequence:
  • NM_000258.3:c.170C>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
probably has functional consequence
Observations:
1

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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000199362Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Nov 3, 2022) 		germlineclinical testing

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

SCV000284301Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jan 22, 2024) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV000579523Center for Human Genetics, University of Leuven
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 9, 2017) 		germlineclinical testing

SCV004843364All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 18, 2023) 		germlineclinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown14not providednot provided108544not providedclinical testing
Caucasiangermlineyes21not providednot providedyesclinical testing

Citations

PubMed

Frequency and spectrum of actionable pathogenic secondary findings in 196 Korean exomes.

Jang MA, Lee SH, Kim N, Ki CS.

Genet Med. 2015 Dec;17(12):1007-11. doi: 10.1038/gim.2015.26. Epub 2015 Apr 9.

PubMed [citation]
PMID:
25856671

Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells.

Ma N, Zhang JZ, Itzhaki I, Zhang SL, Chen H, Haddad F, Kitani T, Wilson KD, Tian L, Shrestha R, Wu H, Lam CK, Sayed N, Wu JC.

Circulation. 2018 Dec 4;138(23):2666-2681. doi: 10.1161/CIRCULATIONAHA.117.032273.

PubMed [citation]
PMID:
29914921
PMCID:
PMC6298866
See all PubMed Citations (24)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000199362.7

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

Description

The p.Ala57Gly variant in MYL3 has been identified in at least 17 individuals with HCM (Lee 2001 PMID: 11174330, Choi 2010 PMID: 20641121, Murakami 2014 (no PMID), Robyns 2020 PMID: 31513939, Chung 2020 PMID: 32380161, Kim 2020 PMID: 32492895, GeneDx pers. comm., Ambry pers. comm., Invitae pers. comm., LMM data) and segregated with disease in 5 affected family members from 2 families (Lee 2001 PMID: 11174330, Choi 2010 PMID: 20641121). It has also been reported by other clinical laboratories in ClinVar (Variation ID 31780) and has been identified in 0.03% (5/18394) of East Asian chromosomes and 0.01% (12/113750) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org), which is higher than the maximum expected allele frequency for a pathogenic variant in the MYL3 gene associated with autosomal dominant HCM. In vivo and in vitro functional studies provide some evidence that this variant impacts protein function; however, these types of assays may not accurately represent biological function (Muthu 2011 PMID: 21885653, Lossie 2012 PMID: 22131351, Kazmierczak 2013 PMID: 23748425, Ma 2018 PMID: 29914921). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, based on the high allele frequency of this variant in the gnomAD population database the clinical significance of the p.Ala57Gly variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate; PP1_Moderate, BS1_Supporting.

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

From Invitae, SCV000284301.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (11)

Description

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 57 of the MYL3 protein (p.Ala57Gly). This variant is present in population databases (rs139794067, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11174330, 20641121, 27532257, 28193612, 29121657, 31513939, 32380161, 33407484). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31780). 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, 23748425). 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.

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

From Center for Human Genetics, University of Leuven, SCV000579523.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Caucasian2not providedyesclinical testingnot provided

Description

ACMG score pathogenic

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not provided1not provided

From All of Us Research Program, National Institutes of Health, SCV004843364.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided14not providednot providedclinical testing PubMed (11)

Description

This missense variant replaces alanine with glycine at codon 57 of the MYL3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). An experimental study has shown that this variant lowers the binding capacity of the MYL3 protein to the myosin lever-arm in vitro (PMID: 22131351). In addition, transgenic mice expressing this variant showed decreased maximal force generation, high levels of heart fibrosis, and hypertrophy compared to wild-type (PMID: 23748425, 32034976). This variant has been reported in a three-generation Korean family affected with hypertrophic cardiomyopathy (PMID: 11174330, 20641121). Among 12 carriers in this family, 5 individuals were affected with late-onset hypertrophic cardiomyopathy, 6 individuals were affected with late-onset atrial fibrillation, heart failure and sudden cardiac death, and one adult individual had normal ECG and echocardiographic findings. This variant has also been reported to show 50% penetrance in a small family affected with hypertrophic cardiomyopathy (PMID: 29121657). This variant has been reported in another five unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 30105547, 32492895, 33495596, 35626289, Irie et al. 2011, doi:10.1016/j.fsigss.2011.08.072). However, this variant has also been identified in 18/251470 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In addition, in multiple case-control studies recently conducted, this variant has not shown a significant association with hypertrophic cardiomyopathy (communication with an external laboratory; ClinVar SCV000199362.6). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided14not providednot providednot provided

Last Updated: May 7, 2024