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

gnomAD frequency: 0.00006  dbSNP: rs202011992

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172455	SCV000051336	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040942	SCV000064633	likely benign	not specified	2018-04-27	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544021	SCV000643965	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-08-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172455	SCV000701159	uncertain significance	not provided	2017-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000172455	SCV000730331	likely benign	not provided	2020-10-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780, 31983221)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769101	SCV000900474	uncertain significance	Cardiomyopathy	2016-05-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000040942	SCV002067988	uncertain significance	not specified	2020-05-06	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002371853	SCV002688464	uncertain significance	Cardiovascular phenotype	2019-12-12	criteria provided, single submitter	clinical testing	The p.N3179S variant (also known as c.9536A>G), located in coding exon 39 of the TTN gene, results from an A to G substitution at nucleotide position 9536. The asparagine at codon 3179 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000172455	SCV003823560	uncertain significance	not provided	2022-09-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040942	SCV005888201	uncertain significance	not specified	2025-01-16	criteria provided, single submitter	clinical testing	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.