NM_001267550.2(TTN):c.9674A>G (p.Asn3225Ser) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Jan 16, 2025
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:: RCV000040942.18

Allele description [Variation Report for NM_001267550.2(TTN):c.9674A>G (p.Asn3225Ser)]

NM_001267550.2(TTN):c.9674A>G (p.Asn3225Ser)

Gene:

TTN:titin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q31.2

Genomic location:

Preferred name:

NM_001267550.2(TTN):c.9674A>G (p.Asn3225Ser)

HGVS:

NC_000002.12:g.178766410T>C
NG_011618.3:g.69393A>G
NM_001256850.1:c.9674A>G
NM_001267550.2:c.9674A>GMANE SELECT
NM_003319.4:c.9536A>G
NM_133378.4:c.9674A>G
NM_133379.5:c.9674A>G
NM_133432.3:c.9536A>G
NM_133437.4:c.9536A>G
NP_001243779.1:p.Asn3225Ser
NP_001254479.2:p.Asn3225Ser
NP_003310.4:p.Asn3179Ser
NP_596869.4:p.Asn3225Ser
NP_596870.2:p.Asn3225Ser
NP_597676.3:p.Asn3179Ser
NP_597681.4:p.Asn3179Ser
LRG_391:g.69393A>G
NC_000002.11:g.179631137T>C
NM_003319.4:c.9536A>G
c.9674A>G

Protein change:

N3179S

Links:

dbSNP: rs202011992

NCBI 1000 Genomes Browser:

rs202011992

Molecular consequence:

NM_001256850.1:c.9674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001267550.2:c.9674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003319.4:c.9536A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133378.4:c.9674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133379.5:c.9674A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133432.3:c.9536A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_133437.4:c.9536A>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
SCV000064633	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely benign (Apr 27, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002067988	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 6, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005888201	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 16, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24503780, 31983221, 30531895, 33500567 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000064633

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely benign
(Apr 27, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002067988

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 6, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005888201

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 16, 2025)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	7	5	not provided	not provided	not provided	clinical testing
not provided	germline	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

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

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000064633.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (1)

Description

The p.Asn3225Ser variant in TTN is classified as likely benign because it has be en identified 0.01% (11/126504) of European chromosomes by the Genome Aggregatio n Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202011992). In add ition, this variant was identified by this laboratory in 2 individuals who carri ed other variants sufficient to explain their cardiomyopathy. One carried a like ly pathogenic variant in TTN and the other carried a likely pathogenic ATCT1 var iant. ACMG/AMP Criteria applied: BS1_Supporting; BP2; BP5.

#	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		7	not provided	5	not provided

From Genetic Services Laboratory, University of Chicago, SCV002067988.1

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

Description

The c.9674A>G sequence change results in an amino acid change, p.Asn3225Ser. This sequence change has been described in the gnomAD database with a low population frequency of 0.00426% (dbSNP rs202011992). The p.Asn3225Ser change affects a highly conserved amino acid residue located in a domain of the TTN protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn3225Ser substitution. This sequence change does not appear to have been previously described in patients with TTN-related disorders. Due to lack of sufficient evidence, the clinical significance of the p.Asn3225Ser change remains unknown at this time.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	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, SCV005888201.2

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

Description

Variant summary: TTN c.9674A>G (p.Asn3225Ser) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251220 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Autosomal Recessive Titinopathy (4e-05 vs 0.00039), allowing no conclusion about variant significance. c.9674A>G has been reported in the literature in individuals affected with cardiomyopathy and left ventricular noncompaction, but was also detected in control cohorts (e.g., Mazzarotto_2020, Mazzarotto_2021, Pugh_2014, Thomson_2019). These reports do not provide unequivocal conclusions about association of the variant with TTN-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31983221, 33500567, 24503780, 30531895). ClinVar contains an entry for this variant (Variation ID: 47673). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: May 25, 2025

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