Submissions for variant NM_001267550.2(TTN):c.41488G>A (p.Val13830Ile)

gnomAD frequency: 0.00045  dbSNP: rs149059189

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000724877	SCV000237153	likely benign	not provided	2020-06-02	criteria provided, single submitter	clinical testing
Invitae	RCV001082051	SCV000286647	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000241687	SCV000319132	uncertain significance	Cardiovascular phenotype	2013-09-25	criteria provided, single submitter	clinical testing	The p.V11262I variant (also known as c.33784G>A) is located in coding exon 174 of the TTN gene. This alteration results from a G to A substitution at nucleotide position 33784. The valine at codon 11262 is replaced by isoleucine, an amino acid with highly similar properties. ​ ​This variant was previously reported in the SNPDatabase as rs149059189. Based on data from the NHLBI Exome Sequencing Project (ESP), the A-allele has an overall frequency of approximately 0.04% (5/12,442), having been observed in 0.12% (5/4078) of African American alleles, and not observed in 8364 European American alleles studied. Based on data from the 1000 Genomes Project, the A-allele has an overall frequency of approximately 0.05% (1/2184). The highest observed frequency was 0.52% (1/194) Luhya chromosomes studied. This amino acid position is poorly conserved in available vertebrate species. This variant is predicted to be benign by PolyPhen in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.V11262I remains unclear.
Eurofins Ntd Llc (ga)	RCV000724877	SCV000332113	uncertain significance	not provided	2015-06-11	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000724877	SCV001146399	likely benign	not provided	2018-10-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798649	SCV002042469	benign	Cardiomyopathy	2020-05-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282012	SCV002571964	likely benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.33784G>A (p.Val11262Ile) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 248378 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3-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 African or African-American origin. To our knowledge, no occurrence of c.33784G>A in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (benign, n = 1; likely benign, n = 3; uncertain significance, n = 2). Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV000724877	SCV003820214	likely benign	not provided	2023-04-04	criteria provided, single submitter	clinical testing