ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.94629A>G (p.Ile31543Met)

gnomAD frequency: 0.00008  dbSNP: rs397517759
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040811 SCV000064502 uncertain significance not specified 2012-10-02 criteria provided, single submitter clinical testing The Ile28975Met variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, and PolyPhen2) suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. Additional information is needed to fully assess the cli nical significance of this variant.
Ambry Genetics RCV000247537 SCV000318280 uncertain significance Cardiovascular phenotype 2013-02-07 criteria provided, single submitter clinical testing There is insufficient or conflicting evidence for classification of this alteration.
Illumina Laboratory Services, Illumina RCV000356392 SCV000420746 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000390504 SCV000420747 likely benign Myopathy, myofibrillar, 9, with early respiratory failure 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina RCV000298221 SCV000420748 benign Tibial muscular dystrophy 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina RCV000353169 SCV000420749 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina RCV000277148 SCV000420750 uncertain significance Dilated cardiomyopathy 1G 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040811 SCV003923262 uncertain significance not specified 2023-03-16 criteria provided, single submitter clinical testing Variant summary: TTN c.86925A>G (p.Ile28975Met) results in a conservative amino acid change located in the A band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 247874 control chromosomes in the gnomAD database, including 1 homozygotes suggesting a benign role for this variant. c.86925A>G has been reported in the literature in individuals affected with cardio myopathy and epilepsy (example: Pugh_2014 and Allen_2021). At-least one of these reports classified the variant as VUS (Pugh_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004786313 SCV005399155 uncertain significance TTN-related myopathy 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (I) 0104 - Dominant Negative is likely a mechanism of disease for this gene since not all truncated transcripts in dilated cardiomyopathy (DCM) undergo nonsense mediated decay (PMID: 25589632). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0112 - Variants in this gene are known to have reduced penetrance of PTC variants in DCM (PMID: 25589632). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to methionine (exon 341). (I) 0251 - Variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (17 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v3 (2 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant is not conserved in mammals with a minor amino acid change. (SB) 0601 - Variant affects at least one well-established (essential) functional domain or motif. Variant located in A band, PSI=1 (PMID: 25589632). (I) 0705 - No comparable variants have previous evidence for pathogenicity. However, a different variant in the same codon resulting in a change to a valine has been reported as VUS (ClinVar). (I) 0804 - Variant has previously been described as variant of uncertain significance in multiple independent cases with inconsistent phenotypes (ClinVar, PMID: 24503780). (I) 0905 - No segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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