NM_001267550.2(TTN):c.66977A>G (p.Lys22326Arg) AND not specified

Germline classification:: Benign/Likely benign (5 submissions)
Last evaluated:: Nov 29, 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:: RCV000040515.18

Allele description [Variation Report for NM_001267550.2(TTN):c.66977A>G (p.Lys22326Arg)]

NM_001267550.2(TTN):c.66977A>G (p.Lys22326Arg)

Genes:

TTN-AS1:TTN antisense RNA 1 [Gene - HGNC]
TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.66977A>G (p.Lys22326Arg)

Other names:

p.K20685R:AAA>AGA

HGVS:

NC_000002.12:g.178580402T>C
NG_011618.3:g.255401A>G
NG_051363.1:g.62576T>C
NM_001256850.1:c.62054A>G
NM_001267550.2:c.66977A>GMANE SELECT
NM_003319.4:c.39782A>G
NM_133378.4:c.59273A>G
NM_133432.3:c.40157A>G
NM_133437.4:c.40358A>G
NP_001243779.1:p.Lys20685Arg
NP_001254479.2:p.Lys22326Arg
NP_003310.4:p.Lys13261Arg
NP_596869.4:p.Lys19758Arg
NP_597676.3:p.Lys13386Arg
NP_597681.4:p.Lys13453Arg
LRG_391t1:c.66977A>G
LRG_391:g.255401A>G
NC_000002.11:g.179445129T>C
NM_001267550.1:c.66977A>G
NM_003319.4:c.39782A>G
c.59273A>G

Protein change:

K13261R

Links:

dbSNP: rs202125813

NCBI 1000 Genomes Browser:

rs202125813

Molecular consequence:

NM_001256850.1:c.62054A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.66977A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.39782A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.59273A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.40157A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.40358A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000064206	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Apr 10, 2012)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000337566	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely benign (Nov 12, 2015)	germline	clinical testing	Citation Link,
SCV001476359	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Benign (Feb 19, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001924097	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002041816	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Nov 29, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23861362, 24503780 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	4	4	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064206.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (1)

Description

Lys19758Arg in exon 266 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (12/3048) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS). Lys19758Arg in exon 266 of TTN (allele frequenc y = 0.4%, 12/3048) **

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		4	not provided	4	not provided

From Eurofins Ntd Llc (ga), SCV000337566.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	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		2	not provided	not provided	not provided

From Athena Diagnostics, SCV001476359.1

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

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

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924097.1

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

#	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		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002041816.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: TTN c.59273A>G (p.Lys19758Arg) results in a conservative amino acid change located in the A-band region of 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 0.00049 in 279656 control chromosomes, predominantly at a frequency of 0.0053 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.59273A>G has been reported in the literature in an African American individual affected with Dilated Cardiomyopathy (Pugh_2014). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 (n=2) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.

#	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

Last Updated: Oct 8, 2024

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