Submissions for variant NM_001267550.2(TTN):c.43244G>A (p.Ser14415Asn)

gnomAD frequency: 0.00012  dbSNP: rs370342831

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040236	SCV000063927	uncertain significance	not specified	2011-12-19	criteria provided, single submitter	clinical testing	The Ser11847Asn variant (TTN) has not been previously reported but has been iden tified by our laboratory in 1 individual with HCM (the role of TTN in HCM is cur rently not understood). Serine (Ser) at position 11847 is moderately conserved a cross evolutionarily distant species and this information is insufficient to pre dict if a change would impact the protein. Computational predictions on the impa ct to the protein are mixed (AlignGVGD = inconclusive, SIFT = pathogenic), thoug h the accuracy of these tools is unknown. Additional information is needed to f ully assess the clinical significance of the Ser11847Asn variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769021	SCV000900394	likely benign	Cardiomyopathy	2023-04-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000838588	SCV000980460	likely benign	not provided	2018-06-07	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040236	SCV002599005	uncertain significance	not specified	2022-09-20	criteria provided, single submitter	clinical testing	Variant summary: TTN c.35540G>A (p.Ser11847Asn) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 247618 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (4.4e-05 vs 0.00039), allowing no conclusion about variant significance. c.35540G>A has been reported in the literature in an individual affected with Dilated Cardiomyopathy (van Lint_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign and another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002399387	SCV002706408	likely benign	Cardiovascular phenotype	2019-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000838588	SCV003818389	uncertain significance	not provided	2020-01-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734562	SCV005363069	uncertain significance	TTN-related disorder	2024-03-08	no assertion criteria provided	clinical testing	The TTN c.43244G>A variant is predicted to result in the amino acid substitution p.Ser14415Asn. This variant was reported as a variant of uncertain significance in an individual with hypertrophic cardiomyopathy (described as p.Ser11847Asn in online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666). This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.