VCV000138345.42 - ClinVar

NM_002474.3(MYH11):c.4522A>G (p.Met1508Val)

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.

(12)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(8); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002474.3(MYH11):c.4522A>G (p.Met1508Val)

Variation ID: 138345 Accession: VCV000138345.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.11 16: 15721478 (GRCh38) [ NCBI UCSC ] 16: 15815335 (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	Oct 2, 2016	Aug 4, 2024	Mar 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002474.3:c.4522A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002465.1:p.Met1508Val	missense
NM_017668.3:c.948-2713T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001040113.2:c.4543A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035202.1:p.Met1515Val	missense
NM_001040114.2:c.4543A>G	NP_001035203.1:p.Met1515Val	missense
NM_001143979.2:c.948-2713T>C		intron variant
NM_022844.3:c.4522A>G	NP_074035.1:p.Met1508Val	missense
NC_000016.10:g.15721478T>C
NC_000016.9:g.15815335T>C
NG_009299.1:g.140553A>G
NG_021210.1:g.83212T>C
LRG_1401:g.140553A>G
LRG_1401t1:c.4522A>G	LRG_1401p1:p.Met1508Val
LRG_1401t2:c.4543A>G	LRG_1401p2:p.Met1515Val
	P35749:p.Met1508Val

... more HGVS ... less HGVS

Protein change

M1515V, M1508V

Other names

p.M1508V:ATG>GTG

Canonical SPDI

NC_000016.10:15721477:T:C

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.00260 (C)

Allele frequency

The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00134

Exome Aggregation Consortium (ExAC) 0.00143

1000 Genomes Project 0.00260

1000 Genomes Project 30x 0.00297

Trans-Omics for Precision Medicine (TOPMed) 0.00472

The Genome Aggregation Database (gnomAD) 0.00480

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00593

Links

ClinGen: CA292313

UniProtKB: P35749#VAR_050206

dbSNP: rs35176378

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.
MYH11		No evidence available	No evidence available	GRCh38 GRCh38 GRCh37	2029	3793
NDE1		-	-	GRCh38 GRCh38 GRCh37	183	1947

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 (3)	criteria provided, multiple submitters, no conflicts	Jan 18, 2014	RCV000126953.17
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jul 20, 2015	RCV000244209.9
Aortic aneurysm, familial thoracic 4	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 27, 2024	RCV000471823.30
Familial thoracic aortic aneurysm and aortic dissection	Benign (2)	criteria provided, multiple submitters, no conflicts	Dec 7, 2022	RCV000769663.13
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV001812085.22

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.
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000306197.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 18, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170484.11 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Nov 03, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745477.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (Mar 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903202.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001279812.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 20226094 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Jul 20, 2015)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000319367.5 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Comment: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance Number of individuals with the variant: 1
Benign (Jan 29, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884170.3 First in ClinVar: Feb 18, 2019 Last updated: Jan 08, 2022
Benign (Dec 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901071.2 First in ClinVar: May 06, 2019 Last updated: Feb 04, 2024
Benign (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000556086.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024
Likely benign (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003917487.11 First in ClinVar: Apr 23, 2023 Last updated: Aug 04, 2024	Comment: MYH11: BS1 Number of individuals with the variant: 6
Benign (May 26, 2015)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000745960.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034138.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

Title	Author	Journal	Year	Link
Myosin individualized: single nucleotide polymorphisms in energy transduction.	Burghardt TP	BMC genomics	2010	PMID: 20226094

Text-mined citations for rs35176378 ...

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_002474.3(MYH11):c.4522A>G (p.Met1508Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35176378 ...