Submissions for variant NM_001267550.2(TTN):c.34864G>A (p.Val11622Ile)

gnomAD frequency: 0.00288  dbSNP: rs202014478

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172679	SCV000055023	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040179	SCV000063870	likely benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing	p.Val10321Ile in exon 149 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.6% (400/67108) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g).
GeneDx	RCV000040179	SCV000237115	benign	not specified	2016-12-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081699	SCV000286598	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247302	SCV000318217	uncertain significance	Cardiovascular phenotype	2013-01-16	criteria provided, single submitter	clinical testing	​The p.V10321I variant (also known as c.30961G>A) is located in coding exon 148 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 30961. The valine at codon 10321 is replaced by isoleucine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase asrs202014478.Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.29% (34/11806), having been observed in 0.14% (5/3650) of African American alleles, and in 0.36% (29/8156) of European American alleles. Based on protein sequence alignment, this amino acid position is conserved in available vertebrate species. In addition, this alteration is predicted to be benign by PolyPhen in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.V10321I remains unclear.
Eurofins Ntd Llc (ga)	RCV000040179	SCV000334864	likely benign	not specified	2015-09-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000040179	SCV000597657	likely benign	not specified	2016-04-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769039	SCV000900412	benign	Cardiomyopathy	2019-03-11	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000172679	SCV001146381	benign	not provided	2019-08-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172679	SCV001152963	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS2
Illumina Laboratory Services, Illumina	RCV001132263	SCV001291918	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	RCV001132264	SCV001291919	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	RCV001132265	SCV001291920	likely benign	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001133178	SCV001292865	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	RCV001133179	SCV001292866	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040179	SCV001426872	benign	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.30961G>A (p.Val10321Ile) results in a conservative amino acid change located in the I-band of the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 236296 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 8 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 benign. To our knowledge, no occurrence of c.30961G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all laboratories classified as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172679	SCV001740746	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172679	SCV001800526	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040179	SCV001917989	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000040179	SCV001954590	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004534895	SCV004747428	likely benign	TTN-related disorder	2019-08-30	no assertion criteria provided	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).