ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.31837C>G (p.Pro10613Ala)

gnomAD frequency: 0.00033  dbSNP: rs200213832
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Total submissions: 14
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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 RCV000040128 SCV000063819 uncertain significance not specified 2012-07-24 criteria provided, single submitter clinical testing The Pro9369Ala variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/8176 Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/), though this could represent a pre symptomatic individual. Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) do not argue for or against an impact to the protein. Additional information is needed to fully assess the clin ical significance of the Pro9369Ala variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000233950 SCV000286572 uncertain significance Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-12-27 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000725168 SCV000334599 uncertain significance not provided 2015-08-24 criteria provided, single submitter clinical testing
Athena Diagnostics RCV000725168 SCV000616056 likely benign not provided 2018-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000725168 SCV000730353 likely benign not provided 2021-03-02 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24503780)
CeGaT Center for Human Genetics Tuebingen RCV000725168 SCV001152989 likely benign not provided 2024-07-01 criteria provided, single submitter clinical testing TTN: BP4
Illumina Laboratory Services, Illumina RCV001134533 SCV001294280 benign Tibial muscular dystrophy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina RCV001134534 SCV001294281 uncertain significance Early-onset myopathy with fatal cardiomyopathy 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001134535 SCV001294282 uncertain significance Dilated cardiomyopathy 1G 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001135959 SCV001295771 benign Myopathy, myofibrillar, 9, with early respiratory failure 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina RCV001135960 SCV001295772 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001135960 SCV001525248 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2J 2020-01-08 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040128 SCV002599001 likely benign not specified 2023-12-11 criteria provided, single submitter clinical testing Variant summary: TTN c.28105C>G (p.Pro9369Ala) results in a non-conservative amino acid change located in the I-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 0.00037 in 247188 control chromosomes, predominantly at a frequency of 0.00076 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.28105C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy and an individual reported with Sudden Unexplained Death (Pugh_2014, Campuzano_2015). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. 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: 24503780, 26516846).Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences RCV004528207 SCV004103586 uncertain significance TTN-related disorder 2023-03-13 criteria provided, single submitter clinical testing The TTN c.28105C>G variant is predicted to result in the amino acid substitution p.Pro9369Ala. This variant has been reported in an individual with dilated cardiomyopathy and interpreted as uncertain significance (Table S3, referred to as g.179554549G>C/NM_133378.4:c.28105C>G, Pugh et al. 2014. PubMed ID: 24503780). This variant is reported in 0.077% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179554549-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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