Submissions for variant NM_001267550.2(TTN):c.27928G>A (p.Val9310Ile)

gnomAD frequency: 0.00003  dbSNP: rs200207722

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185462	SCV000238388	uncertain significance	not specified	2014-03-26	criteria provided, single submitter	clinical testing	Missense variants in the TTN gene are considered 'unclassified' if they are not previously reported in the literature and do not have >1% frequency in the population to be considered a polymorphism. Research indicates that truncating mutations in the TTN gene are expected to account for approximately 25% of familial and 18% of sporadic idiopathic DCM; however, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles. There has been little investigation into non-truncating variants. (Herman D et al. Truncations of titin causing dilated cardiomyopathy. N Eng J Med 366:619-628, 2012) The variant is found in DCM,CARDIOMYOPATHY panel(s).
Invitae	RCV000643771	SCV000765458	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185462	SCV002074480	uncertain significance	not specified	2022-01-30	criteria provided, single submitter	clinical testing	Variant summary: TTN c.24196G>A (p.Val8066Ile) results in a conservative amino acid change located in the I-band region 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 9.3e-05 in 248246 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (9.3e-05 vs 0.00039), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.24196G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory (MYH7 c.2722C>G, p.Leu908Val), providing supporting evidence for a benign role. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.