ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.1714C>T (p.Arg572Trp) (rs142142718)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000552008 SCV000636939 uncertain significance Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-08-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 572 of the ACTN2 protein (p.Arg572Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs142142718, ExAC 0.06%). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 27532257) and an individual affected with dilated cardiomyopathy or with symptoms suggestive of dilated cardiomyopathy (PMID: 24503780). ClinVar contains an entry for this variant (Variation ID: 43914). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036884 SCV000060539 uncertain significance not specified 2011-02-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg572Trp v ariant has not been reported in the literature but has been identified in 1 Blac k DCM proband tested by our laboratory. Please note: we have only sequenced the ACTN2 in 45 Black individuals and healthy control information is unavailable fro m either public databases or scientific literature, such that the full spectrum of benign variation has not yet been defined for this population. Future analysi s could reveal that the Arg572Trp variant is common and therefore unlikely to be pathogenic. However, arginine (Arg) at position 572 is highly conserved across evolutionary distant species, increasing the likelihood that the change is patho genic. In addition, computational analyses (PolyPhen2, SIFT, AlignGVGD) suggest that the variant may impact the protein although this information is not predict ive enough to assume pathogenicity. In summary, the clinical significance of th is variant cannot be determined without further studies.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786083 SCV000924717 uncertain significance not provided 2017-09-22 no assertion criteria provided provider interpretation p.Arg572Trp (c.1714C>T) in exon 15 of the ACTN2 gene (NM_001103.3) Chromosome position: 1:236914827 C / T Based on the information reviewed below, we classify this as a VUS (leaning toward VUS, Probably Benign), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It may be a benign rare variant more common among people with African ancestry such as our patient. The ExAC browser’s “Filtering Allele Frequency” (Whiffin et al. 2017) suggests that this variant is too common to plausibly cause disease. This variant has previously been reported in 2 unrelated cases of cardiomyopathy in the literature. However, there is no published segregation data. The variant was first reported in an individual with dilated cardiomyopathy, or clinical features suggestive of dilated cardiomyopathy, who was tested at the Laboratory for Molecular Medicine (Pugh et al. 2014; PMID: 24503780 & 27532257). In ClinVar, LMM specifies that this proband had African ancestry. It was also identified in an individual affected with hypertrophic cardiomyopathy tested at the Oxford Medical Genetics Laboratories (Walsh et al. 2017 PMID: 27532257). No ethnicity information is provided for the HCM patient. Of note, when Walsh et al. compared variants in ACTN2 for HCM cases and ExAC “controls”, they found no significant excess of rare genetic variation in the HCM cases, suggesting that there is not a solid causal connection between this gene and HCM. This is a nonconservative amino acid change, resulting in the replacement of a positively-charged Arginine with a nonpolar Tryptophan. Arginine at this location is highly conserved across ~100 vertebrate species for which we have data. There are no Likely Pathogenic or Pathogenic variants listed in ClinVar within 10 amino acids to either side, indicating that this region of the protein might be tolerant of change. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant was reported in 16 individuals in the gnomAD database, most of them with African ancestry like our patient. Specifically, the variant was observed in 13 individuals with African ancestry (for the highest allele frequency: 0.054%), 2 with Latino ancestry, and 1 with East Asian ancestry. There are also 3 individuals with a different variant at this location: p.Arg572Gln. gnomAD currently includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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