Submissions for variant NM_001171.6(ABCC6):c.1171A>G (p.Arg391Gly)

gnomAD frequency: 0.00459  dbSNP: rs72653762

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256117	SCV000321360	pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	Recent study (not peer reviewed) including 590 probands with PXE showed a 2.9-fold enrichment of this variant among individuals with PXE versus population controls and incomplete penetrance, whereby only a small portion of probands with the p.(R391G) variant were symptomatic, but showed similar disease severity as probands with bi-allelic pathogenic loss-of-function variants (Szeri et al., 2020); Located in exon 9, a region with high sequence homology with an expressed pseudogene ABCC6P1; however, variant is not present in this pseudogene, which excludes the possibility that the high population frequency of p.(R391G) is due to a sequencing artifact; Arg391 residue is part of the 4th intracellular loop at the cytoplasmic surface of the protein and was suggested to have intramolecular interactions with several other residues and might be involved in the conformational switch of the protein (Szeri et al., 2020; Issa et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15086542, 34440381, 32445016, 11702217, 28102862, 11536079, 16410789, 16086317, 24008425, 14631379, 16835894, 29722917, 17617515, 23485117, 28655553, 31398764, 32818659, 22209248, 29487417, 32039214, 34205333, 32873932, 26135620, 34426522, 32442430, 34148116, 33005041)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455861	SCV000538215	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in an individual with cutanous Pseudoxanthoma Elasticum who also had a multi exon deletion in ABCC6 (Chassing 2004). Also reported in two probands and in one affected twin sibling with generalized arterial calcification of infancy (Nitschke 2012), one of whom also had a frameshift variant. This was the only variant identified in the twins. MAF 0.8% with 3 homozygotes in ExAC.
Eurofins Ntd Llc (ga)	RCV000256117	SCV000700696	uncertain significance	not provided	2017-05-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000256117	SCV000780531	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000499064	SCV000845610	uncertain significance	Autosomal recessive inherited pseudoxanthoma elasticum	2018-08-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000256117	SCV001097502	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288946	SCV002580759	uncertain significance	Arterial calcification, generalized, of infancy, 2	2022-02-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455861	SCV003934758	uncertain significance	not specified	2023-05-19	criteria provided, single submitter	clinical testing	Variant summary: ABCC6 c.1171A>G (p.Arg391Gly) results in a non-conservative amino acid change to a well-conserved residue (HGMD) located in a helix at the cytoplasmic site of transmembrane domain 1 (Szeri_2022) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0056 in 250940 control chromosomes in the gnomAD database, including 5 homozygotes. c.1171A>G has been reported in the literature in many individuals affected with Pseudoxanthoma Elasticum who are compound heterozygous with other pathogenic variants (e.g. Chassaing_2004, Garcia-Fernandez_2008, Ringpfeil_2006, Saeidan_2022, Schulz_2006, Szeri_2002). A modest enrichment in the frequency of the variant in affected individuals over the general population suggests the possibility that it may be associated with disease with a low penetrance, possibly mediated by interactions with unidentified variants in an interacting partner protein of ABCC6 (Szeri_2022). These reports do not provide unequivocal conclusions about association of the variant with Pseudoxanthoma Elasticum. At least two publications report experimental evidence evaluating an impact on protein function, finding no damaging effect of this variant on expression, subcellular localization, or functional activity (Szeri_2022, Saeidan_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36317459, 15086542, 16410789, 16835894, 18513494, 16835894). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations, and classified it as likely benign (n=2), pathogenic (n=1), and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV004576935	SCV005061128	uncertain significance	Pseudoxanthoma elasticum, forme fruste		criteria provided, single submitter	clinical testing	The observed missense c.1171A>G(p.Arg391Gly) variant in ABCC6 gene has been reported in homozygous or compound heterozygous state in multiple individuals affected with Pseudoxanthoma elasticum (Szeri F, et. al., 2022). This variant is present with an allele frequency of 0.5% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely Benign/ Pathogenic/Likely Pathogenic/Uncertain Significance. The amino acid change p.Arg391Gly in ABCC6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 391 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816464	SCV005071498	uncertain significance	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016653	SCV005645507	uncertain significance	Autosomal recessive inherited pseudoxanthoma elasticum; Pseudoxanthoma elasticum, forme fruste; Arterial calcification, generalized, of infancy, 2	2024-05-11	criteria provided, single submitter	clinical testing
PXE International	RCV000499064	SCV000588952	uncertain significance	Autosomal recessive inherited pseudoxanthoma elasticum	2021-03-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000256117	SCV001551237	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ABCC6 p.Arg391Gly variant was identified in 10 of 852 proband chromosomes (frequency: 0.0117) from individuals with Pseudoxanthoma Elasticum (PXE) and Generalized Arterial Calcification of Infancy (GACI) (Nitschke_2012_PMID: 22209248; Chassaing_2004_PMID: 15086542; Pfendner_2007_PMID:17617515; Schulz_2006_PMID: 16835894; Miksch_2006_PMID:168358954). The R391G variant was also identified in 3 of 7 families affected with PXE, found in the compound heterozygous state. In two of these families the clinical manifestation of PXE was less severe, and one individual was asymptomatic but may not have presented with disease yet (Ringpfeil_2006_PMID:16410789). Therefore the R391G may contribute to a less severe form of the disorder. The variant was also identified in dbSNP (ID: rs72653762), LOVD 3.0 and ClinVar (classified as pathogenic by GeneDx and PXE International and as a VUS by EGL Genetics, Laboratory for Molecular Medicine, CeGaT Praxis fuer Humangenetik Tuebingen and Genomic Research Center, Shahid Beheshti University of Medical Sciences). The variant was identified in control databases in 1545 of 282338 chromosomes (5 homozygous) at a frequency of 0.005472 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was observed in the following populations: European (non-Finnish) in 1021 of 128772 chromosomes (freq: 0.007929), South Asian in 235 of 30614 chromosomes (freq: 0.007676), Other in 44 of 7218 chromosomes (freq: 0.006096), European (Finnish) in 95 of 25122 chromosomes (freq: 0.003782), Latino in 108 of 35440 chromosomes (freq: 0.003047), African in 40 of 24870 chromosomes (freq: 0.001608) and Ashkenazi Jewish in 2 of 10358 chromosomes (freq: 0.000193), while the variant was not observed in the East Asian population. The p.Arg391 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004535232	SCV004728868	likely pathogenic	ABCC6-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The ABCC6 c.1171A>G variant is predicted to result in the amino acid substitution p.Arg391Gly. This variant has been reported in the heterozygous, compound heterozygous, and homozygous states, as well as in the presence of other ABCC6 variants (phase not established), in individuals with pseudoxanthoma elasticum (PXE) of variable severity and onset (Chassaing et al. 2004. PubMed ID: 15086542; Misksch et al. 2005. PubMed ID: 16086317; Ringpfeil et al. 2006. PubMed ID: 16410789, Schulz et al. 2006. PubMed ID: 16835894, Pfendner et al. 2007. PubMed ID: 17617515; Legrand et al. 2017. PubMed ID: 28102862; De Vilder et al. 2018. PubMed ID: 29722917; Boraldi et al. 2020. PubMed ID: 32039214; Issa et al. 2020. PubMed ID: 32442430). It has been reported in the heterozygous state in the absence of a second variant in at least one individual from an ischemic stroke cohort (Table S3, De Vilder et al. 2018. PubMed ID: 29722917). It has been reported in the heterozygous state with and without the presence of a second ABCC6 variant (phase not established), in a limited number of individuals with generalized calcification of infancy (GACI) and/or vascular anomalies (Nitschke et al. 2012. PubMed ID: 22209248; Li et al. 2014. PubMed ID: 24008425; Mattassi et al. 2018. PubMed ID: 28655553). A recent study reported this variant along with a second variant in 3 individuals with late onset PXE consisting of only ocular features with an onset of 80 years of age or older (Issa et al. 2020. PubMed ID: 32442430). This variant is thought to be a low penetrance hypomorphic allele capable of resulting in disease when combined with a severe pathogenic variant on the opposite allele (in trans) (Issa et al. 2020. PubMed ID: 32442430). More recently, the penetrance of this variant was hypothesized to be only 2%; however, when penetrant, it manifests a similar disease severity and progression to what two fully penetrant loss of function variants cause (Szeri et al. 2022. PubMed ID: 36317459). In an updated version of gnomAD (v4), this variant has an allele frequency of 0.84% in individuals of Middle Eastern descent, including 57 homozygous individuals globally, which is likely too frequent to be a primary cause of disease. This variant is interpreted as likely pathogenic with incomplete penetrance.