NM_001267550.2(TTN):c.69383C>A (p.Ser23128Tyr) AND not specified

Germline classification:: Benign/Likely benign (5 submissions)
Last evaluated:: Mar 8, 2024
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:: RCV000176782.21

Allele description [Variation Report for NM_001267550.2(TTN):c.69383C>A (p.Ser23128Tyr)]

NM_001267550.2(TTN):c.69383C>A (p.Ser23128Tyr)

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.69383C>A (p.Ser23128Tyr)

Other names:

p.S21487Y:TCT>TAT

HGVS:

NC_000002.12:g.178576952G>T
NG_011618.3:g.258851C>A
NG_051363.1:g.59126G>T
NM_001256850.1:c.64460C>A
NM_001267550.2:c.69383C>AMANE SELECT
NM_003319.4:c.42188C>A
NM_133378.4:c.61679C>A
NM_133432.3:c.42563C>A
NM_133437.4:c.42764C>A
NP_001243779.1:p.Ser21487Tyr
NP_001254479.2:p.Ser23128Tyr
NP_003310.4:p.Ser14063Tyr
NP_596869.4:p.Ser20560Tyr
NP_597676.3:p.Ser14188Tyr
NP_597681.4:p.Ser14255Tyr
LRG_391t1:c.69383C>A
LRG_391:g.258851C>A
NC_000002.11:g.179441679G>T
NM_001267550.1:c.69383C>A

Protein change:

S14063Y

Links:

dbSNP: rs72646882

NCBI 1000 Genomes Browser:

rs72646882

Molecular consequence:

NM_001256850.1:c.64460C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.69383C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.42188C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.61679C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.42563C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.42764C>A - 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
SCV000237472	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jul 27, 2017)	germline	clinical testing	Citation Link,
SCV000332824	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Benign (Jul 17, 2015)	germline	clinical testing	Citation Link,
SCV000710948	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (May 18, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001146474	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	benign (Mar 8, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001370716	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (May 11, 2020)	germline	clinical testing	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	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	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

Details of each submission

From GeneDx, SCV000237472.3

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

Description

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.

#	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 Eurofins Ntd Llc (ga), SCV000332824.3

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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000710948.2

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

Description

p.Ser20560Tyr in exon 273 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.8% (192/24008) of African chrom osomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs72646882).

#	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		1	not provided	1	not provided

From Athena Diagnostics, SCV001146474.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001370716.1

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

Description

Variant summary: TTN c.61679C>A (p.Ser20560Tyr) results in a non-conservative amino acid change located in the A-band domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 279450 control chromosomes, predominantly at a frequency of 0.0079 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.61679C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (4x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as likely 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: Jan 19, 2025

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