Submissions for variant NM_014391.3(ANKRD1):c.838A>G (p.Ile280Val)

gnomAD frequency: 0.00004  dbSNP: rs144770680

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150156	SCV000197042	likely benign	not specified	2013-11-05	criteria provided, single submitter	clinical testing	Ile280Val in exon 8 of ANKRD1: This variant is not expected to have clinical sig nificance due to a lack of conservation across species, including mammals. Of no te, the variant amino acid, valine (Val), has been identified in 7 other mammals (lemur, rat, mouse, horse, cow, alpaca, and opossum) despite high nearby amino acid conservation. In addition, computational analyses (AlignGVGD, PolyPhen2, SI FT) do not suggest a high likelihood of impact to the protein. Finally, it has b een identified in 3/8600 European American chromosomes from a broad population b y the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP r s144770680). Ile280Val in exon 8 of ANKRD1 (rs144770680; allele frequency = 3/8 600) **
GeneDx	RCV000766742	SCV000520826	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy; however, specific clinical information was not provided (PMID: 19608031, 31983221, 28082330); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19608032, 23299917, 31983221, 34400558, 28082330, 23572067, 19608031)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823178	SCV000964027	uncertain significance	ANKRD1-related dilated cardiomyopathy	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 280 of the ANKRD1 protein (p.Ile280Val). This variant is present in population databases (rs144770680, gnomAD 0.007%). This missense change has been observed in individual(s) with ANKRD1-related conditions (PMID: 19608031, 31983221). ClinVar contains an entry for this variant (Variation ID: 162746). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ANKRD1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ANKRD1 function (PMID: 19608031, 23572067). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798466	SCV002043483	uncertain significance	Cardiomyopathy	2019-09-05	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447504	SCV004175477	uncertain significance	Primary dilated cardiomyopathy	2021-03-16	criteria provided, single submitter	clinical testing