NM_000258.2(MYL3):c.517A>G (p.Met173Val) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Jan 25, 2016)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000258.2(MYL3):c.517A>G (p.Met173Val)]

NM_000258.2(MYL3):c.517A>G (p.Met173Val)

MYL3:myosin light chain 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000258.2(MYL3):c.517A>G (p.Met173Val)
Other names:
  • NC_000003.12:g.46858426T>C
  • NG_007555.2:g.28744A>G
  • NM_000258.2:c.517A>G
  • NP_000249.1:p.Met173Val
  • LRG_395t1:c.517A>G
  • LRG_395:g.28744A>G
  • LRG_395p1:p.Met173Val
  • NC_000003.11:g.46899916T>C
  • c.517A>G
  • p.(Met173Val)
Protein change:
Leiden Muscular Dystrophy (MYL3): MYL3_00007; dbSNP: rs199474708
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000258.2:c.517A>G - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
functional variant [Sequence Ontology: SO:0001536]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000059681Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Uncertain significance
(Sep 24, 2012)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000208889GeneDxcriteria provided, single submitter
Uncertain significance
(Jan 25, 2016)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided42not providednot providednot providedclinical testing



Shared genetic causes of cardiac hypertrophy in children and adults.

Morita H, Rehm HL, Menesses A, McDonough B, Roberts AE, Kucherlapati R, Towbin JA, Seidman JG, Seidman CE.

N Engl J Med. 2008 May 1;358(18):1899-908. doi: 10.1056/NEJMoa075463. Epub 2008 Apr 9.

PubMed [citation]

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]

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000059681.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (2)


Variant classified as Uncertain Significance - Favor Pathogenic. The Met173Val variant (MYL3) has been reported in the literature in one individual with early onset HCM, segregated with disease in two affected relatives (including one obligate carrier), and was absent from 1360 control chromosomes (Morita 2008, LMM data). This variant has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS); this low frequency is consistent with a disease causing role but insufficient to establish this with confidence. Methionine (Met) at position 173 is highly conserved in mammals, however computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the normal function of the protein. Additional studies are needed to fully assess the clinical significance of this variant.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided2not provided

From GeneDx, SCV000208889.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


The M173V mutation has been previously published in association with childhood-onset familial left ventricular hypertrophy and was not identified in more than 1000 chromosomes of unaffected persons (Morita H et al., 2008). Furthermore, the M173V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although M173V, is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties; Morita et al. (2008) reported M173V is highly conserved throughout mammalian evolution and predicted that this missense residue alters protein structure. Consequently, a missense mutation in a nearby residue (E177G) has been reported in HGMD in association with HCM substitution (Stenson P et al., 2009), further supporting the functional importance of this region of the protein. In summary, M173V in the MYL3 gene is interpreted as a disease-causing mutation.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2018