Submissions for variant NM_014391.3(ANKRD1):c.417C>A (p.Phe139Leu)

gnomAD frequency: 0.00043  dbSNP: rs201398260

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038852	SCV000062530	uncertain significance	not specified	2012-10-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Phe139Leu varia nt in ANKRD1 has been identified by our laboratory in one individual with DCM, b ut did not segregate with disease in 1 affected relative. In addition, this vari ant has been identified in 1/186 Finnish chromosomes by the 1000 Genomes Sequenc ing Project (http://1000genomes.org; dbSNP rs201398260), though this could repre sent a presymptomatic individual. Phenylalanine (Phe) at this position is not co nserved in mammals or evolutionarily distant species, suggesting that a change a t this position may be tolerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. Although this data supports that the Phe139Leu variant may be benign, additional studies are needed to fully asse ss its clinical significance.
GeneDx	RCV000767133	SCV000535718	uncertain significance	not provided	2019-05-06	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26383259)
Invitae	RCV001514558	SCV001722430	benign	ANKRD1-related dilated cardiomyopathy	2021-11-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798125	SCV002043481	benign	Cardiomyopathy	2021-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038852	SCV005040432	likely benign	not specified	2024-03-04	criteria provided, single submitter	clinical testing	Variant summary: ANKRD1 c.417C>A (p.Phe139Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 250530 control chromosomes (gnomAD). The observed variant frequency is approximately 21-fold of the estimated maximal expected allele frequency for a pathogenic variant in ANKRD1 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.417C>A has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with Dilated Cardiomyopathy and in cases of sudden cardiac death, without strong evidence for causality (e.g. Pugh_2014, Hertz_2016, Vahatalo_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26383259, 24503780, 35087879). ClinVar contains an entry for this variant (Variation ID: 45634). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV004639131	SCV005136521	likely benign	Cardiovascular phenotype	2024-03-21	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.