Submissions for variant NM_001082486.2(ACD):c.22G>A (p.Val8Ile)

gnomAD frequency: 0.00053  dbSNP: rs149365469

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000503600	SCV000593016	likely benign	not specified	2020-01-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694462	SCV000822910	uncertain significance	Dyskeratosis congenita, autosomal dominant 6	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 94 of the ACD protein (p.Val94Ile). This variant is present in population databases (rs149365469, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dyskeratosis congenita–like phenotype (PMID: 30064976). ClinVar contains an entry for this variant (Variation ID: 434071). 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 ACD protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACD function (PMID: 30064976). 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.
GeneDx	RCV001702497	SCV002504526	likely benign	not provided	2021-04-07	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000503600	SCV002551734	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003243155	SCV003944284	uncertain significance	Inborn genetic diseases	2023-03-24	criteria provided, single submitter	clinical testing	The c.280G>A (p.V94I) alteration is located in exon 1 (coding exon 1) of the ACD gene. This alteration results from a G to A substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV001702497	SCV004139989	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ACD: BP4
GenomeConnect - Invitae Patient Insights Network	RCV000694462	SCV001749492	not provided	Dyskeratosis congenita, autosomal dominant 6		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-25-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702497	SCV001928757	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001702497	SCV001965078	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003962366	SCV004794188	likely benign	ACD-related disorder	2021-05-26	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).