ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.57593A>G (p.Asn19198Ser)

gnomAD frequency: 0.00005  dbSNP: rs199787097
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000656988 SCV000228179 uncertain significance not provided 2015-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000656988 SCV000237334 uncertain significance not provided 2020-02-14 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 195842; Landrum et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012)
Invitae RCV000642811 SCV000764498 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 19198 of the TTN protein (p.Asn19198Ser). There is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs199787097, ExAC 0.01%). This variant has not been reported in the literature in individuals with TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 195842). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192386 SCV001360459 uncertain significance not specified 2019-08-12 criteria provided, single submitter clinical testing Variant summary: TTN c.49889A>G (p.Asn16630Ser) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic exonic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.7e-05 in 240600 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.49889A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000656988 SCV001714643 uncertain significance not provided 2020-08-05 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000656988 SCV002770598 uncertain significance not provided 2022-02-21 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002492762 SCV002778363 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 2021-08-03 criteria provided, single submitter clinical testing

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