ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs202011992
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Total submissions: 10
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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.

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