Submissions for variant NM_001267550.2(TTN):c.37432C>T (p.Pro12478Ser)

gnomAD frequency: 0.00143  dbSNP: rs200992277

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000082395	SCV000055016	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040185	SCV000063876	benign	not specified	2017-10-23	criteria provided, single submitter	clinical testing	The p.Pro10574Ser variant has been identified in 2% (101/5052) of South Asian c hromosomes, including 6 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). BA1
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083903	SCV000286617	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-22	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040185	SCV000337399	benign	not specified	2018-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000082395	SCV000977120	benign	not provided	2018-06-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852867	SCV000995601	likely benign	Primary dilated cardiomyopathy	2017-02-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133068	SCV001292754	benign	Tibial muscular dystrophy	2017-05-25	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001133069	SCV001292755	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-25	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	RCV001133070	SCV001292756	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-05-25	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001133071	SCV001292757	likely benign	Dilated cardiomyopathy 1G	2017-05-25	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001136516	SCV001296355	likely benign	Early-onset myopathy with fatal cardiomyopathy	2017-05-25	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040185	SCV004020317	benign	not specified	2023-06-01	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31720C>T (p.Pro10574Ser) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 51728 control chromosomes, predominantly at a frequency of 0.02 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 31.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Cardiomyopathy phenotype (0.00063), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.31720C>T has been reported in the literature in individuals affected with Cardiomyopathy (e.g., Pughes_2014), and at least one case of sudden unexplained death (e.g., Sanchez_2016), however without strong evidence for causality in all cases. These reports therefore do not provide unequivocal conclusions about association of the variant with 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, 27930701). Eight ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments (benign, n = 5; likely benign, n = 2; VUS, n = 1). Based on the evidence outlined above, the variant was classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000082395	SCV001798144	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040185	SCV001917944	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000040185	SCV001966539	benign	not specified		no assertion criteria provided	clinical testing