Submissions for variant NM_001267550.2(TTN):c.67604G>A (p.Ser22535Asn)

gnomAD frequency: 0.00012  dbSNP: rs375676529

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203942	SCV000261414	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2015-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces serine with asparagine at codon 22535 of the TTN protein (c.67604G>A). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs375676529, ExAC 0.02%) but has not been reported in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000245927	SCV000318921	likely benign	Cardiovascular phenotype	2020-07-07	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Eurofins Ntd Llc (ga)	RCV000291189	SCV000334584	uncertain significance	not provided	2015-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000291189	SCV001794538	likely benign	not provided	2019-02-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798687	SCV002042609	uncertain significance	Cardiomyopathy	2020-05-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000291189	SCV003818530	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401109	SCV004121820	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: TTN c.59900G>A (p.Ser19967Asn) results in a conservative amino acid change located in the A-band region of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 247796 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Dilated Cardiomyopathy (6.9e-05 vs 0.00039), allowing no conclusion about variant significance. c.59900G>A has been reported in the literature in at least one individual affected with Dilated Cardiomyopathy (Mazzarotto_2020). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 31983221). Six ClinVar submitters have assessed the variant since 2014: four classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000291189	SCV004150310	uncertain significance	not provided	2025-02-01	criteria provided, single submitter	clinical testing	TTN: PM2, BP4
PreventionGenetics, part of Exact Sciences	RCV004530235	SCV004116040	uncertain significance	TTN-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The TTN c.67604G>A variant is predicted to result in the amino acid substitution p.Ser22535Asn. This variant was reported in a large cohort study of individuals with dilated cardiomyopathy (Reported as chr2:g.179444320 in Supp. Table 3 Mazzarotto et al 2020. PubMed ID: 31983221). This variant is reported in 0.012% 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.