VCV000138342.42 - ClinVar

NM_002474.3(MYH11):c.4242T>G (p.Ala1414=)

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.

(19)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002474.3(MYH11):c.4242T>G (p.Ala1414=)

Variation ID: 138342 Accession: VCV000138342.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.11 16: 15724284 (GRCh38) [ NCBI UCSC ] 16: 15818141 (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	Sep 29, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002474.3:c.4242T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002465.1:p.Ala1414=	synonymous
NM_017668.3:c.*33A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_001040113.2:c.4263T>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035202.1:p.Ala1421=	synonymous
NM_001040114.2:c.4263T>G	NP_001035203.1:p.Ala1421=	synonymous
NM_001143979.2:c.*33A>C		3 prime UTR
NM_022844.3:c.4242T>G	NP_074035.1:p.Ala1414=	synonymous
NC_000016.10:g.15724284A>C
NC_000016.9:g.15818141A>C
NG_009299.1:g.137747T>G
NG_021210.1:g.86018A>C
LRG_1401:g.137747T>G
LRG_1401t1:c.4242T>G	LRG_1401p1:p.Ala1414=
LRG_1401t2:c.4263T>G	LRG_1401p2:p.Ala1421=

... more HGVS ... less HGVS

Protein change

Other names

p.A1414A:GCT>GCG

Canonical SPDI

NC_000016.10:15724283:A:C

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.

0.41014 (C)

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

Trans-Omics for Precision Medicine (TOPMed) 0.45544

The Genome Aggregation Database (gnomAD) 0.45713

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.45898

1000 Genomes Project 30x 0.40881

1000 Genomes Project 0.41014

Links

ClinGen: CA292304 dbSNP: rs2075511 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	2037	3810
NDE1		-	-	GRCh38 GRCh38 GRCh37	186	1959

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	Apr 4, 2013	RCV000126950.22
Familial thoracic aortic aneurysm and aortic dissection	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000250056.17
Lissencephaly, Recessive	Benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000316233.14
Aortic aneurysm, familial thoracic 4	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000609871.27
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Nov 19, 2014	RCV000617695.10
Lissencephaly 4	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001116324.13
Megacystis-microcolon-intestinal hypoperistalsis syndrome 2	Benign (1)	criteria provided, single submitter	Sep 5, 2021	RCV001775609.10
not provided	Benign (3)	criteria provided, multiple submitters, no conflicts	Nov 30, 2023	RCV001705917.21
Visceral myopathy 2	Benign (1)	criteria provided, single submitter	Sep 5, 2021	RCV001775610.10

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: SCV000306193.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Lissencephaly, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000395264.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
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: SCV000910506.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (Apr 04, 2013)	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: SCV000269269.2 First in ClinVar: May 29, 2016 Last updated: Oct 02, 2016	Comment: Ala1421Ala in exon 32 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue … (more) Ala1421Ala in exon 32 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 46.4% (3990/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2075511). (less) Number of individuals with the variant: 25
Benign (Jan 12, 2018)	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: SCV000395263.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Lissencephaly 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001274382.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Nov 19, 2014)	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: SCV000738268.3 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018	Comment: This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA … (more) This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Number of individuals with the variant: 1
Benign (Jun 19, 2015)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000317691.3 First in ClinVar: Oct 02, 2016 Last updated: May 31, 2020	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 (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001838647.2 First in ClinVar: Sep 26, 2021 Last updated: Aug 05, 2023
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002014360.1 First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Visceral myopathy 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002014362.1 First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021
Benign (Sep 05, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Megacystis-microcolon-intestinal hypoperistalsis syndrome 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002014361.1 First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021
Benign (Feb 01, 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: SCV001716970.4 First in ClinVar: Jun 15, 2021 Last updated: Feb 14, 2024
Benign (Nov 30, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885763.9 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial thoracic aortic aneurysm and aortic dissection (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004821231.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 80868
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005290185.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	Aortic aneurysm, familial thoracic 4 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733496.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Nov 19, 2014)	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: SCV000745962.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001969215.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

Ala1421Ala in exon 32 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 46.4% (3990/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2075511).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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 rs2075511 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_002474.3(MYH11):c.4242T>G (p.Ala1414=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs2075511 ...