VCV000046522.26 - ClinVar

NM_033118.4(MYLK2):c.173C>A (p.Ala58Asp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_033118.4(MYLK2):c.173C>A (p.Ala58Asp)

Variation ID: 46522 Accession: VCV000046522.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q11.21 20: 31820246 (GRCh38) [ NCBI UCSC ] 20: 30408049 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 8, 2015	Feb 28, 2024	Jan 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_033118.4:c.173C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_149109.1:p.Ala58Asp	missense
NC_000020.11:g.31820246C>A
NC_000020.10:g.30408049C>A
NG_012847.1:g.5872C>A
LRG_392:g.5872C>A
LRG_392t1:c.173C>A	LRG_392p1:p.Ala58Asp

... more HGVS ... less HGVS

Protein change

A58D

Other names

p.A58D:GCC>GAC

Canonical SPDI

NC_000020.11:31820245:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00519 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00070

Trans-Omics for Precision Medicine (TOPMed) 0.00084

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092

The Genome Aggregation Database (gnomAD), exomes 0.00191

Exome Aggregation Consortium (ExAC) 0.00198

1000 Genomes Project 30x 0.00437

1000 Genomes Project 0.00519

Links

ClinGen: CA138522 dbSNP: rs138130914 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYLK2		-	-	GRCh38 GRCh37	639	663

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Nov 17, 2020	RCV000039784.10
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Mar 26, 2019	RCV000172570.9
Cardiomyopathy	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jun 28, 2018	RCV000770567.4
Hypertrophic cardiomyopathy 1	Benign (1)	criteria provided, single submitter	Jan 19, 2024	RCV001081175.8
Hypertrophic cardiomyopathy	Likely benign (1)	criteria provided, single submitter	-	RCV001293152.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051017.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 2
Likely benign (Feb 18, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000063473.6 First in ClinVar: May 03, 2013 Last updated: May 30, 2018	Comment: p.Ala58Asp in exon 3 of MYLK2: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (150/16508) of … (more) p.Ala58Asp in exon 3 of MYLK2: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (150/16508) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138130914). (less) Number of individuals with the variant: 6
Benign (Jan 19, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291169.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Nov 17, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001448539.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Comment: Variant summary: MYLK2 c.173C>A (p.Ala58Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: MYLK2 c.173C>A (p.Ala58Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 250664 control chromosomes, predominantly at a frequency of 0.0097 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 390 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.173C>A in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. 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 benign (2x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Mar 26, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236020.9 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 23861362)
Likely benign (Apr 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995695.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Benign (Jun 28, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV000902016.2 First in ClinVar: May 06, 2019 Last updated: May 31, 2020
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy Affected status: yes Allele origin: unknown	Genetics and Genomics Program, Sidra Medicine Accession: SCV001434142.1 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743448.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (Oct 15, 2014)	no assertion criteria provided Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280391.1 First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016	Comment: Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more) Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966817.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

p.Ala58Asp in exon 3 of MYLK2: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (150/16508) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs138130914).

Comment:

Variant summary: MYLK2 c.173C>A (p.Ala58Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 250664 control chromosomes, predominantly at a frequency of 0.0097 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 390 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYLK2 causing Hypertrophic Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.173C>A in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. 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 benign (2x) / likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.

Comment:

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs138130914 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_033118.4(MYLK2):c.173C>A (p.Ala58Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs138130914 ...