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NM_000258.3(MYL3):c.433A>G (p.Asn145Asp) AND Hypertrophic cardiomyopathy

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Mar 4, 2023
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:
RCV001359764.5

Allele description [Variation Report for NM_000258.3(MYL3):c.433A>G (p.Asn145Asp)]

NM_000258.3(MYL3):c.433A>G (p.Asn145Asp)

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.433A>G (p.Asn145Asp)
HGVS:
  • NC_000003.12:g.46859523T>C
  • NG_007555.2:g.27647A>G
  • NM_000258.3:c.433A>GMANE SELECT
  • NP_000249.1:p.Asn145Asp
  • LRG_395t1:c.433A>G
  • LRG_395:g.27647A>G
  • NC_000003.11:g.46901013T>C
  • NM_000258.2:c.433A>G
  • p.Asn145Asp
Protein change:
N145D
Links:
dbSNP: rs1204710752
NCBI 1000 Genomes Browser:
rs1204710752
Molecular consequence:
  • NM_000258.3:c.433A>G - missense variant - [Sequence Ontology: SO:0001583]
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
SCV001555646Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 19, 2022) 		germlineclinical testing

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

SCV004843325All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Mar 4, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.

Harper AR, Goel A, Grace C, Thomson KL, Petersen SE, Xu X, Waring A, Ormondroyd E, Kramer CM, Ho CY, Neubauer S; HCMR Investigators., Tadros R, Ware JS, Bezzina CR, Farrall M, Watkins H.

Nat Genet. 2021 Feb;53(2):135-142. doi: 10.1038/s41588-020-00764-0. Epub 2021 Jan 25.

PubMed [citation]
PMID:
33495597
PMCID:
PMC8240954
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001555646.3

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

Description

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 145 of the MYL3 protein (p.Asn145Asp). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1051693). This variant has not been reported in the literature in individuals affected with MYL3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%).

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

From All of Us Research Program, National Institutes of Health, SCV004843325.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces asparagine with aspartic acid at codon 145 of the MYL3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 2/31392 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

Last Updated: May 7, 2024