NM_033118.4(MYLK2):c.1514C>T (p.Thr505Ile) AND Hypertrophic cardiomyopathy 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 11, 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:: RCV001337640.7

Allele description [Variation Report for NM_033118.4(MYLK2):c.1514C>T (p.Thr505Ile)]

NM_033118.4(MYLK2):c.1514C>T (p.Thr505Ile)

Gene:

MYLK2:myosin light chain kinase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20q11.21

Genomic location:

Preferred name:

NM_033118.4(MYLK2):c.1514C>T (p.Thr505Ile)

Other names:

p.Thr505Ile

HGVS:

NC_000020.11:g.31831792C>T
NG_012847.1:g.17418C>T
NM_033118.3:c.1514C>T
NM_033118.4:c.1514C>TMANE SELECT
NP_149109.1:p.Thr505Ile
LRG_392t1:c.1514C>T
LRG_392:g.17418C>T
NC_000020.10:g.30419595C>T

Protein change:

T505I

Links:

dbSNP: rs144359857

NCBI 1000 Genomes Browser:

rs144359857

Molecular consequence:

NM_033118.4:c.1514C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypertrophic cardiomyopathy 1
Synonyms:: Familial hypertrophic cardiomyopathy 1; MYH7-Related Familial Hypertrophic Cardiomyopathy
Identifiers:: MONDO: MONDO:0008647; MedGen: C3495498; OMIM: 192600

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Lactiplantibacillus plantarum strain YC1.2 Scaffold49_1, whole genome shotgun sequence
gi|2329264064|ref|NZ_JANEZM01000005 gnl|WGS:NZ_JANEZM01|Scaffold49_1

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001531248	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004811878	Clinical Genomics Program, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 11, 2021)	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

SCV001531248

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 2020)

germline

clinical testing

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

SCV004811878

Clinical Genomics Program, Stanford Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 11, 2021)

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	yes	1	not provided	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

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Invitae, SCV001531248.4

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

Description

This variant has not been reported in the literature in individuals with MYLK2-related conditions. This variant is present in population databases (rs144359857, ExAC 0.009%). This sequence change replaces threonine with isoleucine at codon 505 of the MYLK2 protein (p.Thr505Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

#	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 Clinical Genomics Program, Stanford Medicine, SCV004811878.1

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

Description

The p.Thr505Ile variant in the MYLK2 gene has not been previously reported in association with disease. This variant has been identified in 4/251,486 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of hypertrophic cardiomyopathy. Computational tools do not predict that the p.Thr505Ile variant impacts protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Thr505Ile variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2]

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

Last Updated: Apr 15, 2024

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