Submissions for variant NM_001267550.2(TTN):c.24454G>A (p.Val8152Ile)

gnomAD frequency: 0.00004  dbSNP: rs397517507

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040002	SCV000063693	uncertain significance	not specified	2015-02-03	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Val6908Ile va riant in TTN has been identified by our laboratory in 1 adult with HCM, who also carried an pathogenic HCM variant. The Val6908Ile variant has been identified i n 2/16502 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs397517507). Valine (Val) at position 6908 i s not conserved in evolution and several species have an isoleucine (Ile) at thi s position, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Val6908Ile variant is uncertain, the presence of the variant amino acid in other species suggests that it is more likely to be be nign.
GeneDx	RCV001703897	SCV000238347	likely benign	not provided	2018-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000248793	SCV000318541	uncertain significance	Cardiovascular phenotype	2013-04-04	criteria provided, single submitter	clinical testing	There is insufficient or conflicting evidence for classification of this alteration.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040002	SCV004020327	likely benign	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: TTN c.20722G>A (p.Val6908Ile) results in a conservative amino acid change located in the I-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 0.0003 in 326038 control chromosomes, predominantly at a frequency of 0.0011 within the Japanese subpopulation, including 1 homozygote (gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing a dilated cardiomyopathy phenotype (3.9e-04), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.20722G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (ALMS1 c.427C>T, p.Q143X; MYH7 c.4259G>A, p.R1420Q; both observed in internal testing), providing supporting evidence for a benign role. The following publication was ascertained in the context of this evaluation (PMID: 33179747). Two ClinVar submitters (evaluation after 2014) have cited the variant; one submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.