Submissions for variant NM_001267550.2(TTN):c.72302C>A (p.Thr24101Asn)

gnomAD frequency: 0.00010  dbSNP: rs192962624

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152220	SCV000201004	likely benign	not specified	2015-02-03	criteria provided, single submitter	clinical testing	p.Thr21533Asn in exon 275 of TTN: This variant is not expected to have clinical significance it has been identified in 0.44% (37/8486) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs192962624).
Invitae	RCV000642992	SCV000764679	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152220	SCV000855120	likely benign	not specified	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133041	SCV001292727	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-08-01	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	RCV001133042	SCV001292728	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	RCV001133043	SCV001292729	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.
Illumina Laboratory Services, Illumina	RCV001133044	SCV001292730	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). 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	RCV001136490	SCV001296329	benign	Tibial muscular dystrophy	2017-08-01	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.
CeGaT Center for Human Genetics Tuebingen	RCV001311958	SCV001502353	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	TTN: BP4
GeneDx	RCV001311958	SCV001803434	likely benign	not provided	2021-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336305	SCV002635126	likely benign	Cardiovascular phenotype	2018-08-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152220	SCV004020353	likely benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.64598C>A (p.Thr21533Asn) results in a non-conservative amino acid change located in the A-band region 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 0.00039 in 248272 control chromosomes, predominantly at a frequency of 0.0044 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11.26 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 East Asian origin. c.64598C>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy, however the variant was classified as benign in the publication in which it was reported (e.g., Guelly_2021). This report therefore does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Co-occurrences with other pathogenic variants have been reported (ALMS1 c.427C>T, p.Q143X; MYH7 c.4259G>A, p.R1420Q; both observed via internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 33552729). Six ClinVar submitters (evaluation after 2014) have cited the variant; five submitters classified the variant as likely benign, and one submitter classified the variant as both uncertain significance and benign in the context of two different conditions. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486674	SCV004240096	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935279	SCV004754933	likely benign	TTN-related condition	2021-02-15	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Genetics, Academic Medical Center	RCV000152220	SCV001920821	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001311958	SCV001967252	likely benign	not provided		no assertion criteria provided	clinical testing