NM_000258.3(MYL3):c.460C>T (p.Arg154Cys) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 28, 2021
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:: RCV000036024.7

Allele description [Variation Report for NM_000258.3(MYL3):c.460C>T (p.Arg154Cys)]

NM_000258.3(MYL3):c.460C>T (p.Arg154Cys)

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.460C>T (p.Arg154Cys)

HGVS:

NC_000003.12:g.46859496G>A
NG_007555.2:g.27674C>T
NM_000258.3:c.460C>TMANE SELECT
NP_000249.1:p.Arg154Cys
NP_000249.1:p.Arg154Cys
LRG_395t1:c.460C>T
LRG_395:g.27674C>T
LRG_395p1:p.Arg154Cys
NC_000003.11:g.46900986G>A
NM_000258.2:c.460C>T
c.460C>T

Protein change:

R154C

Links:

dbSNP: rs143852164

NCBI 1000 Genomes Browser:

rs143852164

Molecular consequence:

NM_000258.3:c.460C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000059676	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Apr 13, 2015)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8673105, 25637381, 23283745, 24033266
SCV001478608	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 28, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23396983, 23283745, 25637381, 25132132, 27532257, 28301460, 32906206 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000059676

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Apr 13, 2015)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001478608

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 28, 2021)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	7	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.

Poetter K, Jiang H, Hassanzadeh S, Master SR, Chang A, Dalakas MC, Rayment I, Sellers JR, Fananapazir L, Epstein ND.

Nat Genet. 1996 May;13(1):63-9.

PubMed [citation]

PMID:: 8673105

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (9)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000059676.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (4)

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg154Cys variant in MYL3 has been previously reported in 1 heterozygous Chinese individu al with HCM (Zou 2013). This variant has also been identified by our laboratory in 1 homozygous Bangladeshi infant with RCM, 1 heterozygous African American adu lt with HCM, and in 1 heterozygous Iranian adult with HCM, and was found to segr egate with disease in 1 heterozygous affected relative. This variant has also be en identified in 1/67688 European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs143852164). Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. In addition, a different amino acid change at this position (p.Arg154His) h as also been reported in several individuals with HCM (Poetter 1996, LMM unpubli shed data), supporting that a change at this position may not be tolerated. In s ummary, while there is some suspicion for a pathogenic role, the clinical signif icance of the p.Arg154Cys variant is uncertain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		7	not provided	3	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001478608.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: MYL3 c.460C>T (p.Arg154Cys) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251410 control chromosomes (gnomAD v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.460C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (HCM), however, in most of these cases without strong evidence for causality (e.g. Zou_2013, Lopes_2013, Wang_2014, Walsh_2017). The variant was also reported to be found in large scale population based sequencing projects, but no phenotype was provided for these individuals (Amendola_2015, Narang_2020). These reports therefore do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different missense variant affecting the same amino acid residue (R154H) has been reported in association with HCM (HGMD), but was also found in several controls (gnomAD). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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

Last Updated: Sep 29, 2024

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