Submissions for variant NM_001267550.2(TTN):c.94507G>A (p.Ala31503Thr)

gnomAD frequency: 0.00004  dbSNP: rs375657115

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000560368	SCV000643926	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618293	SCV000736605	uncertain significance	Cardiovascular phenotype	2016-06-10	criteria provided, single submitter	clinical testing	The p.A22438T variant (also known as c.67312G>A), located in coding exon 167 of the TTN gene, results from a G to A substitution at nucleotide position 67312. The alanine at codon 22438 is replaced by threonine, an amino acid with similar properties, and is located in the A-band region of the N2-B isoform of the titin protein. This variant was previously reported in the SNPDatabase as rs375657115. Based on data from ExAC, the A allele has an overall frequency of < 0.01% (9/103545). The highest observed frequency was 0.02%% (3/11198) of Latino alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/12030) total alleles studied and 0.01% (1/8236) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Athena Diagnostics Inc	RCV000993510	SCV001146540	uncertain significance	not provided	2019-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000993510	SCV001820072	likely benign	not provided	2018-12-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798890	SCV002043069	uncertain significance	Cardiomyopathy	2020-12-07	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252162	SCV002522840	uncertain significance	See cases	2021-10-06	criteria provided, single submitter	clinical testing	ACMG classification criteria: BP4
Revvity Omics, Revvity	RCV000993510	SCV003818531	uncertain significance	not provided	2022-06-02	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227786	SCV003925268	uncertain significance	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2022-01-25	criteria provided, single submitter	clinical testing	The c.94507G>A (p.Ala31503Thr) missense variant in the TTN gene has not been reported in affected individuals in the literature. The variant has 0.00005042 allele frequency in the gnomAD (v2.1.1 and v3.1.2) database (14 out of 277666 heterozygous alleles, no homozygotes)suggesting it is not a common benign variant in the populations represented in that database. This variant is reported as a variant of uncertain significance and likely benign in the ClinVar database (Variation ID: 467664). The variant affects a highly conserved residue (Ala31503) located in the A-band domain of TTN protein (PMID:25589632) and multiple in silico tools provide conflicting predictions about the potential pathogenicity of this variant (CADD score = 35, REVEL score = 0.336). Based on the available evidence, the heterozygous c.94507G>A (p.Ala31503Thr) missense variant identified in the TTN gene is reported as a Variant of Uncertain Significance.