ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.2588G>C (p.Gly863Ala)

gnomAD frequency: 0.00445  dbSNP: rs76157638
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Total submissions: 39
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000085494 SCV000226568 pathogenic not provided 2016-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg RCV000008328 SCV000281847 pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085494 SCV000321344 pathogenic not provided 2022-04-12 criteria provided, single submitter clinical testing Most common allele among individuals with Stargardt disease in Northern Europe, representing roughly 20-30% of disease associated alleles (Maugeri et al., 1999).; RNA studies demonstrated that the c.2588 G>C nucleotide change results in the utilization of an alternate splice site, which could produce an abnormal protein lacking the Gly863 residue (aka p.G863del) (Maugeri et al., 1999); Published functional studies demonstrate that G863A has minimal effect on ATP hydrolysis, but significantly reduces interaction of the nucleotide binding domain 1 of the ABCA4 protein with 11-cis-retinal (Biswas-Fiss et al., 2012); One study proposes G863A exhibits pathogenicity only when observed in cis with the common N1868I variant (Zernant et al., 2017); This variant is associated with the following publications: (PMID: 25082885, 25884411, 25346251, 25444351, 25712131, 25922843, 25097241, 9054934, 28446513, 28248825, 27939946, 28044389, 30643219, 30609409, 30718709, 30215852, 28559085, 32845050, 31456290, 25283059, 24082139, 24154662, 25333069, 11017087, 20981092, 22264887, 12192456, 11919200, 25363634, 23144455, 10612508, 23695285, 24713488, 25681002, 28327576, 26247787, 10090887, 28041643, 28341476, 29555955, 3002862, 29310964, 29431110, 29162642, 30563929, 29925512, 32467599, 31980526, 32036094, 32581362, 34426522, 34570182, 32619608, 32913387, 32815999, 32037395, 11527935)
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000008329 SCV000538010 likely pathogenic Cone-rod dystrophy 3 2015-10-23 criteria provided, single submitter clinical testing he c.2588G>C (p.Gly863Ala) missense variant has been reported in several individuals with Stargardt disease (Maugeri A et al., 1999) as well as advanced cone and rod dysfunction (Gerth et al. 2002). It has been seen in trans with other known pathogenic variants in the ABCA4 gene of affected individuals (Heathfield L et al. 2013). In addition, in vitro studies showed that the function of this variant is highly attenuated (Biswas-Fiss et al. 2012). The frequency of this variant in the population databases is lower than the disease allele frequency for the disease and the ancestral amino acid is conserved throughout evolution. Together, the c.2588G>C (p.Gly863Ala) missense variant meets our criteria for Likely Pathogenic
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000787486 SCV000711736 pathogenic Stargardt disease 2018-04-10 criteria provided, single submitter clinical testing The p.Gly863Ala variant in ABCA4 has been reported in >25 individuals with Starg ardt disease in compound heterozygous state with a second ABCA4 variant (Allikme ts 1997, Maugeri 1999, Zhang 1999, Heathfield 2013), and segregated with disease in 3 affected relatives in one family (Zhang 1999). Available evidence suggests that p.Gly863Ala is a mild variant and causes disease when there is a severe va riant on the other allele. This variant has also been identified in 0.79% (998/1 26588) of European chromosomes by the Genome Aggregation Consortium (gnomAD, htt p://gnomad.broadinstitute.org; dbSNP rs76157638). This frequency is consistent w ith the p.Gly863Ala variant being one of the most common ABCA4 variants in patie nts with Stargardt disease in the European population. This variant was demonstr ated to cause aberrant splicing and lead to deletion of the glycine residue at p osition 863 (p.Gly863del) in half of the transcripts from this allele and the mi ssense p.Gly863Ala change in the other half in patient cells (Maugeri 1999). Bot h of these variants had impaired protein activity in in vitro studies (Maugeri 1 999, Sun 2000, Suarez 2002). In summary, this variant meets our criteria to be c lassified as pathogenic for Stargardt disease in an autosomal recessive manner b ased upon its co-occurrence in trans with other pathogenic variants in patients and functional evidence. ACMG/AMP Criteria applied: PM3_Very Strong, PS3_Moderat e, PP1.
Ambry Genetics RCV000623365 SCV000742856 pathogenic Inborn genetic diseases 2014-09-11 criteria provided, single submitter clinical testing The c.2588G>C (p.G863A) alteration is located in exon 17 (coding exon 17) of the ABCA4 gene. This alteration results from a G to C substitution at nucleotide position 2588, causing the glycine (G) at amino acid position 863 to be replaced by an alanine (A). The heterozygous missense change is somewhat rare in population databases:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the ABCA4 c.2588G>C alteration was observed in 68 among 13006 total alleles studied (0.52%). The alteration was observed in the 1000 Genomes Project in 1 among 2098 total alleles studied (0.05%). Based on data from the Genome Aggregation Database (gnomAD), the c.2588G>C alteration was observed among 0.43% (1202/276994) of total alleles studied, having been observed in 0.79% (998/126588) European (non-Finnish) alleles. Rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012; please note that some variants may appear to be rare due to ethnic underrepresentation in the database)._x000D_ _x000D_ IF USED, PULL THESE INTO REFERENCES:_x000D_ Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. The alteration has been observed in affected individuals: _x000D_ The c.2588G>C alteration has been observed in multiple individuals with retinal dystrophy (Maugeri. 2002). It one of the highest frequency autosomal recessive disease mutation in European populations (Maugeri. 2002). The alteration is conserved throughout evolution:_x000D_ The p.G863 amino acid is completetly conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ Functional analysis demonstrated that the p.G863A alteration significantly decreased the rates of nucleotide hydrolysis as well as the binding affinities of the protein (Suárez, 2002) In silico prediction is conflicting:_x000D_ The p.G863A alteration is predicted to be benign by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic.
Mendelics RCV000008328 SCV001135352 pathogenic Severe early-childhood-onset retinal dystrophy 2022-05-27 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000085494 SCV001156938 likely pathogenic not provided 2023-11-03 criteria provided, single submitter clinical testing The ABCA4 c.2588G>C; p.Gly863Ala variant (rs76157638) is reported in the medical literature in individuals with ABCA4-related diseases in the homozygous or compound heterozygous state (Bertelsen 2014, Birtel 2018, Duncker 2015, Khan 2018, Zernant 2017). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 7879) but is also listed in the European (non-Finnish) population with an allele frequency of 0.8% (1012/1209076 alleles, including 7 homozygotes) in the Genome Aggregation Database. This variant has been described as a European founder variant and is implicated as a mild pathogenic variant (Maugeri 1999, Zernant 2017). The glycine at this position is highly conserved but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. However, the variant has also been shown to cause an alternative splice removing one amino acid (Maugeri 1999). Considering available information, this variant is classified as likely pathogenic but may result in a milder clinical phenotype. References: Bertelsen M et al. Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies. Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824. Duncker T et al. Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy. Ophthalmology. 2015 Feb;122(2):345-55. Khan KN et al. Early Patterns of Macular Degeneration in ABCA4-Associated Retinopathy. Ophthalmology. 2018 May;125(5):735-746. Maugeri A et al. The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease. Am J Hum Genet. 1999 Apr;64(4):1024-35. Zernant J et al. Frequent hypomorphic alleles account for a significant fraction of ABCA4 disease and distinguish it from age-related macular degeneration. J Med Genet. 2017 Jun;54(6):404-412.
Invitae RCV000085494 SCV001211627 pathogenic, low penetrance not provided 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 863 of the ABCA4 protein (p.Gly863Ala). This variant is present in population databases (rs76157638, gnomAD 0.8%), including at least one homozygous and/or hemizygous individual. This variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance).
Blueprint Genetics RCV000505063 SCV001241506 pathogenic Retinal dystrophy 2019-08-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085494 SCV001245777 pathogenic not provided 2024-03-01 criteria provided, single submitter clinical testing ABCA4: PM3:Very Strong, PM2:Supporting, PP3, PS3:Supporting
Institute of Human Genetics, University of Leipzig Medical Center RCV000008328 SCV001440306 pathogenic Severe early-childhood-onset retinal dystrophy 2023-01-31 criteria provided, single submitter clinical testing This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.5693G>A and NM_000350.3:c.1411G>A Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000085494 SCV001447808 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000787487 SCV001950198 pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Gly863Ala variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Revvity Omics, Revvity RCV000085494 SCV002019744 pathogenic not provided 2023-06-28 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV000008328 SCV002556399 pathogenic Severe early-childhood-onset retinal dystrophy 2020-07-20 criteria provided, single submitter clinical testing Although common this variant has been reported in the compound-heterozygous state in several individuals and families affected with Stargardt disease and retinitis pigmentosa (PMID: 10612508, 10634594, 10090887, 12192456, 9054934, 23695285, 26247787, 25097241, 28041643). However, studies suggest that this is a mild variant that may only cause disease when in combination with a severe, pathogenic ABCA4 variant (PMID: 10090887). ClinVar contains an entry for this variant (Variation ID: 7879). Experimental studies have shown that this variant results in the production of two transcripts: one that lacks glycine 863 and the other with the Gly863Ala missense change (PMID: 10090887). Additional functional studies have shown that this missense change affects nucleotide hydrolysis and reduces the interaction of ABCA4 with 11-cis-retinal (PMID: 11919200, 23144455, 11017087). In summary, this variant is reported to cause autosomal recessive Stargardt disease and retinitis pigmentosa. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the ABCA4 gene, and as it may not result in disease in the homozygous state, it has been classified as Pathogenic (low penetrance).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000787486 SCV002572288 pathogenic Stargardt disease 2022-08-24 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.2588G>C (p.Gly863Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site and three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (e.g. Maugeri_1999). The variant produces a mixture of two different transcripts, one where the use of a cryptic 3' acceptor site causes a 3bp deletion (resulting in deletion of Gly863), and the other unaffected by splicing (resulting in Gly863Ala). The variant allele was found at a frequency of 0.0044 in 251244 control chromosomes, predominantly at a frequency of 0.008 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA4 causing Stargardt Disease phenotype (0.0014), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. However, c.2588G>C has been reported in the literature in the compound heterozygous state in many individuals affected with Stargardt Disease, including in at least one family where it segregated with the disease phenotype (e.g. Maugeri_1999, Zhang_1999, Heathfield_2013, Weisschuh_2020). It has been proposed that c.2588G>C is a mild founder variant in the western European population, which causes Stargardt Disease only in combination with a severe pathogenic variant on the second allele (e.g. Maugeri_1999). Several publications report experimental evidence evaluating an impact on protein function and have found that both Gly863del and Gly863Ala reduce ATPase activity and that Glu863Ala severely impairs interaction with 11-cis-retinal (e.g. Sun_2000, Suarez_2002, Biswas-Fiss_2012). Many submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and the overwhelming majority classified the variant as either pathogenic (n= 14) or likely pathogenic (n=6). Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center RCV000008328 SCV002581194 pathogenic Severe early-childhood-onset retinal dystrophy 2021-12-20 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000008328 SCV002769539 pathogenic Severe early-childhood-onset retinal dystrophy 2021-05-06 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy, Stargardt disease 1 (MIM#248200) and cone-rod dystrophy (MIM#604116). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected siblings can have variable age of onset and severity of disease (PMID:31522899). 0200 - Variant is predicted to result in a missense amino acid change from glycine to alanine. This variant also leads to aberrant splicing resulting in the in-frame deletion of this residue (p.(Gly863del)) in approximately 50% of transcripts (PMID:10090887). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2, European subpopulation) <0.01 for a recessive condition (1200 heterozygotes, 7 homozygotes). (SP) 0309 - An alternative amino acid change p.(Gly863Glu) at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Nucleotide Binding Domain 1 (NBD1) (PMID: 11444963). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The frequently reported p.[Gly863Ala, Gly863del] variant has strong evidence supporting pathogenicity when in cis with p.(Asn1868Ile) and in trans with a second pathogenic variant. This variant is unlikely to be disease-causing on its own, however the complex allele is fully penetrant and is associated with mild to moderate disease with variable phenotype, depending on the variant on the opposite allele (ClinVar, PMID:9054934, 28044389, 28446513, 32278709). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregates with disease, in a compound heterozygous state with a second pathogenic allele, in at least 5 families in the literature (PMID: 10612508, 31522899). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant leads to reduced protein expression, ATP-binding affinity, and ATP hydrolysis in in vitro studies (PMID: 11017087, 11919200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University of Leipzig Medical Center RCV003224856 SCV003921105 pathogenic Retinitis pigmentosa 19 2023-03-07 criteria provided, single submitter clinical testing This variant was identified together with NM_000350.3:c.2828G>A._x000D_ Criteria applied: PM3_VSTR, PS3_MOD, PM5, PP1, PP3
PreventionGenetics, part of Exact Sciences RCV004532312 SCV004113554 pathogenic ABCA4-related disorder 2024-01-18 criteria provided, single submitter clinical testing The ABCA4 c.2588G>C variant is predicted to result in the amino acid substitution p.Gly863Ala. This variant is also predicted to alter splicing based on available splicing prediction programs (Alamut Visual Plus v1.6.1). This variant is the first nucleotide of exon 17 and a functional study using RT-PCR analysis confirmed that this variant results in a mixture of predicted proteins either lacking one amino acid (p.Gly863del) or carrying the p.Gly863Ala substitution (Maugeri et al. 1999. PubMed ID: 10090887). This variant is reported in 0.78% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 7 homozygous individuals, which is evidence that this variant does not cause disease in the homozygous state. Several studies have supported that this variant is mild and only causes Stargardt disease (STGD) when in trans (on the opposite chromosome) with a severe ABCA4 pathogenic variant (Maugeri et al. 1999. PubMed ID: 10090887; Allikmets et al. 1997. PubMed ID: 9054934; Papaioannou et al. 2000. PubMed ID: 10634594; Suárez et al. 2002. PubMed ID: 11919200). This variant has also been found in cis (on the same chromosome) with another pathogenic variant (c.6088C>T, p.Arg2030*) in two siblings, who carried another pathogenic variant in trans (Song et al. 2015. PubMed ID: 26247787). Functional studies demonstrated that this variant results in a decrease of both basal and retinal-stimulated ATPase activity (Sun et al. 2000. PubMed ID: 11017087). This variant is interpreted as pathogenic.
OMIM RCV000008328 SCV000028536 pathogenic Severe early-childhood-onset retinal dystrophy 2008-07-01 no assertion criteria provided literature only
OMIM RCV000008329 SCV000028537 pathogenic Cone-rod dystrophy 3 2008-07-01 no assertion criteria provided literature only
Retina International RCV000085494 SCV000117631 not provided not provided no assertion provided not provided
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000415097 SCV000492965 uncertain significance Abnormal macular morphology; Peripheral neuropathy 2013-11-28 flagged submission clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505063 SCV000598951 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000008328 SCV000598952 likely pathogenic Severe early-childhood-onset retinal dystrophy 2015-01-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787486 SCV000926452 pathogenic Stargardt disease 2018-04-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787487 SCV000926453 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000787768 SCV000926773 pathogenic Cone-rod dystrophy 2018-04-01 no assertion criteria provided research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet RCV000505063 SCV000926779 pathogenic Retinal dystrophy 2018-04-01 no assertion criteria provided research
Sharon lab, Hadassah-Hebrew University Medical Center RCV000787487 SCV001160859 likely pathogenic Retinitis pigmentosa 2019-06-23 no assertion criteria provided research
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198385 SCV001369306 uncertain significance Age related macular degeneration 2 2016-01-01 flagged submission clinical testing This variant was classified as: Uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000085494 SCV001739756 likely pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535670 SCV001749733 not provided Cone-rod dystrophy 3; Retinitis pigmentosa 19; Age-related macular degeneration no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 02-21-2020 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.
Clinical Genetics, Academic Medical Center RCV000085494 SCV001926098 likely pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000085494 SCV001954981 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000085494 SCV001969328 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein RCV001198385 SCV002029211 likely pathogenic Age related macular degeneration 2 2021-10-04 no assertion criteria provided clinical testing

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