VCV000046680.35 - ClinVar

NM_001267550.2(TTN):c.21044C>T (p.Ala7015Val)

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.

(25)

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_001267550.2(TTN):c.21044C>T (p.Ala7015Val)

Variation ID: 46680 Accession: VCV000046680.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q31.2 2: 178724331 (GRCh38) [ NCBI UCSC ] 2: 179589058 (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	Jul 6, 2014	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001267550.2:c.21044C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001254479.2:p.Ala7015Val	missense
NM_001256850.1:c.20093C>T	NP_001243779.1:p.Ala6698Val	missense
NM_003319.4:c.13282+13751C>T		intron variant
NM_133378.4:c.17312C>T	NP_596869.4:p.Ala5771Val	missense
NM_133432.3:c.13657+13751C>T		intron variant
NM_133437.4:c.13858+13751C>T		intron variant
NC_000002.12:g.178724331G>A
NC_000002.11:g.179589058G>A
NG_011618.3:g.111472C>T
LRG_391:g.111472C>T
LRG_391t1:c.21044C>T

... more HGVS ... less HGVS

Protein change

A7015V, A5771V, A6698V

Other names

p.A5771V:GCA>GTA

Canonical SPDI

NC_000002.12:178724330:G: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.

0.03574 (A)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00265

The Genome Aggregation Database (gnomAD) 0.00666

Trans-Omics for Precision Medicine (TOPMed) 0.00686

Exome Aggregation Consortium (ExAC) 0.01645

The Genome Aggregation Database (gnomAD), exomes 0.01653

1000 Genomes Project 30x 0.03232

1000 Genomes Project 0.03574

Links

ClinGen: CA282793 dbSNP: rs72648960 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.
TTN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	12026	32050
LOC126806428	-	-	-	GRCh38	-	195

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 (9)	criteria provided, multiple submitters, no conflicts	Nov 9, 2020	RCV000039950.38
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Aug 10, 2012	RCV000253287.9
Myopathy, myofibrillar, 9, with early respiratory failure	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2021	RCV000287787.15
Tibial muscular dystrophy	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2021	RCV000323022.15
Early-onset myopathy with fatal cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2021	RCV000345071.15
Autosomal recessive limb-girdle muscular dystrophy type 2J	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 10, 2021	RCV000376615.15
Dilated cardiomyopathy 1G	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000380025.13
Autosomal recessive limb-girdle muscular dystrophy type 2J Dilated cardiomyopathy 1G	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV000469937.18
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Dec 17, 2015	RCV000770084.10
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jun 26, 2019	RCV000993397.13

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 (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	not specified Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051704.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 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: 13
Benign (Sep 01, 2012)	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: SCV000063641.6 First in ClinVar: May 03, 2013 Last updated: May 30, 2018	Comment: 3.1% (26/8230) of Eur Amer chrom in ESP Number of individuals with the variant: 24
Benign (Jun 26, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV001146336.1 First in ClinVar: Jan 19, 2020 Last updated: Jan 19, 2020	Publications: PubMed (1) PubMed: 27868399
Benign (Aug 10, 2012)	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: SCV000317503.5 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	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 (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1G Autosomal recessive limb-girdle muscular dystrophy type 2J Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000555582.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024
Benign (Jan 09, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169613.11 First in ClinVar: Jun 23, 2014 Last updated: Apr 03, 2017	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 (Jun 10, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332028.3 First in ClinVar: Dec 06, 2016 Last updated: May 30, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN Number of individuals with the variant: 1 Sex: mixed
Benign (Dec 17, 2015)	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 Study: Canadian Open Genetics Repository Accession: SCV000901510.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1G Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000424379.3 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 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Early-onset myopathy with fatal cardiomyopathy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000424381.3 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 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Myopathy, myofibrillar, 9, with early respiratory failure Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000424380.3 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 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Tibial muscular dystrophy Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000424378.3 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 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2J Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000424376.3 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)
Likely benign (Nov 09, 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: SCV001448316.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020
Likely 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: SCV005260081.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Sep 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2J Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002099891.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022
Benign (Sep 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myopathy, myofibrillar, 9, with early respiratory failure Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002099892.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022
Benign (Sep 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Early-onset myopathy with fatal cardiomyopathy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002099893.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022
Benign (Sep 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tibial muscular dystrophy Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002099894.1 First in ClinVar: Mar 05, 2022 Last updated: Mar 05, 2022
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000153192.2 First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided 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: SCV001932511.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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: SCV001972766.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798780.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001920880.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955616.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
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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.

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 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:

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
Electron Microscopy Pathology of ADSSL1 Myopathy.	Park HJ	Journal of clinical neurology (Seoul, Korea)	2017	PMID: 27868399
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TTN	-	-	-	-

Text-mined citations for rs72648960 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001267550.2(TTN):c.21044C>T (p.Ala7015Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72648960 ...