NM_001267550.2(TTN):c.227G>C (p.Gly76Ala) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: May 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000325596.41

Allele description [Variation Report for NM_001267550.2(TTN):c.227G>C (p.Gly76Ala)]

NM_001267550.2(TTN):c.227G>C (p.Gly76Ala)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.227G>C (p.Gly76Ala)

HGVS:

NC_000002.12:g.178802206C>G
NG_011618.3:g.33597G>C
NM_001256850.1:c.227G>C
NM_001267550.2:c.227G>CMANE SELECT
NM_003319.4:c.227G>C
NM_133378.4:c.227G>C
NM_133379.5:c.227G>C
NM_133432.3:c.227G>C
NM_133437.4:c.227G>C
NP_001243779.1:p.Gly76Ala
NP_001254479.2:p.Gly76Ala
NP_003310.4:p.Gly76Ala
NP_596869.4:p.Gly76Ala
NP_596870.2:p.Gly76Ala
NP_597676.3:p.Gly76Ala
NP_597681.4:p.Gly76Ala
LRG_391:g.33597G>C
NC_000002.11:g.179666933C>G

Protein change:

G76A

Links:

dbSNP: rs138750421

NCBI 1000 Genomes Browser:

rs138750421

Molecular consequence:

NM_001256850.1:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133379.5:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.227G>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000341903	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (May 25, 2017)	germline	clinical testing	Citation Link,
SCV001473169	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 12, 2019)	germline	clinical testing	Citation Link,
SCV001770125	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Oct 11, 2018)	germline	clinical testing	Citation Link,
SCV002496619	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2024)	germline	clinical testing	Citation Link,
SCV003822203	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Eurofins Ntd Llc (ga), SCV000341903.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473169.1

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

Description

The TTN c.227G>C; p.Gly76Ala variant (rs138750421; ClinVar Variation ID: 287944)]is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of the p.Gly76Ala variant cannot be determined with certainty. References: Begay RL et al. Role of Titin Missense Variants in Dilated Cardiomyopathy. J Am Heart Assoc. 2015 Nov 13;4(11). Herman DS et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med. 2012 Feb 16;366(7):619-28.

#	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

From GeneDx, SCV001770125.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002496619.19

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	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		4	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003822203.2

#	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	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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