Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Biesecker Lab/Clinical Genomics Section, |
RCV000172455 | SCV000051336 | uncertain significance | not provided | 2013-06-24 | criteria provided, single submitter | research | |
Laboratory for Molecular 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 |
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 |
RCV000172455 | SCV000701159 | uncertain significance | not provided | 2017-02-06 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
RCV000769101 | SCV000900474 | uncertain significance | Cardiomyopathy | 2016-05-20 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
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, |
RCV000172455 | SCV003823560 | uncertain significance | not provided | 2022-09-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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. |