rs117687681
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PM5PP3BP4_ModerateBS1_SupportingBS2_Supporting
The NM_000071.3(CBS):c.1105C>T(p.Arg369Cys) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R369H) has been classified as Pathogenic.
Frequency
Consequence
NM_000071.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 68Hom.: 0 Cov.: 0 FAILED QC
GnomAD3 exomes AF: 0.00307 AC: 758AN: 246960Hom.: 5 AF XY: 0.00296 AC XY: 398AN XY: 134310
GnomAD4 exome AF: 0.00426 AC: 180AN: 42276Hom.: 5 Cov.: 0 AF XY: 0.00367 AC XY: 83AN XY: 22632
GnomAD4 genome 0.00 AC: 0AN: 70Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 40
ClinVar
Submissions by phenotype
Classic homocystinuria Uncertain:7
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Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (838 heterozygotes, 5 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (4 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. This variant is located within the active core (PMID: 30380942) in the PALP domain (PDB, Decipher) (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a histidine has also been reported as VUS in a patient with homocystinuria (ClinVar). Functional studies showed that a change to proline (not seen in patients) was shown to result in a phenotype on yeast, whereas the change to histidine did not (PMID: 22267502). (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been previously reported as VUS in individuals with homocystinuria. (ClinVar, PMID: 29650765). (N) 1002 - Functional evidence is conflicting. Studies in different systems, such as yeast and mammals cells showed discrepant results in protein folding and enzyme activity (PMID: 9361025, PMID: 18950795). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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not provided Uncertain:5Benign:1Other:1
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CBS: PS3:Supporting, BS2 -
Identified in association with neural tube defects (NTD) in published literature (PMID: 29205322, 31139930); Multiple in vitro functional analyses of this variant in various expression systems have yielded inconsistent conclusions regarding pathogenicity (PMID: 18950795, 20506325, 22069143, 22267502); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20981092, 10364517, 10338090, 20506325, 12124992, 9361025, 25087612, 22267502, 18950795, 15319318, 15192637, 22069143, 29650765, 22612060, 34426522, 26990548, 19819175, 28152038, 25331909, 34074348, 39582727, Sharo2022[Preprint], 36588553, 36385415, 32245022, 31301157, 30165906, 18708589, 29205322, 31139930, 37443081, 34636997, 38532509) -
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The CBS c.1105C>T; p.Arg369Cys variant (rs117687681, ClinVar Variation ID: 212860) is reported in the literature in individuals affected with homocystinuria, several of whom carried an additional pathogenic variant (Kim 1997, Gaustadnes 2002, Kluijtmans 1999). However, this variant is also found in the general population with an overall allele frequency of 0.3% (838/278330 alleles, including 5 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.972). Functional studies present conflicting results, with in vitro analyses suggesting reduced enzyme activity (Hnizda 2012, Kozich 2010), while complementation studies in yeast indicate function comparable to wildtype (Kim 1997, Mayfield 2012). Due to conflicting information, the clinical significance of the p.Arg369Cys variant is uncertain at this time. References: Gaustadnes M et al. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26. PMID: 12124992. Hnizda A et al. Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Innherit Metab dis 2012; 35:469-477. PMID: 22069143. Kim et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997; 6(13): 2213-2221. PMID: 9361025. Kluijtmans et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet. 1999 Jul;65(1):59-67. PMID: 10364517. Kozich V et al. Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity. Hum Mutat 2010; 31(7):809-819. PMID: 20506325. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics 2012; 190:1309-1323. PMID: 22267502. -
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
PP3 -
not specified Uncertain:1
Variant summary: CBS c.1105C>T (p.Arg369Cys) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) 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 0.0031 in 246960 control chromosomes in the gnomAD database, including 5 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CBS causing Homocystinuria (0.0031 vs 0.003), allowing no conclusion about variant significance. c.1105C>T has been reported in the literature in individuals affected with Cystathionine beta synthase deficiency (CBSD) (e.g. Kim_1997, Kluijtmans_1999, Gaustadnes_2002, Janosick_2009). In one patient, this variant co-occurred in cis with another potentially pathogenic missence variant resulting in a complete loss of enzymatic activity and a severe disease phenotype (Kluijtmans_1999). However, the sole contribution of this variant to the associated pathophysiology could not be determined. Additionally, other possible causes of homocyctinurea, such as mutations in MTHFR, MTR, MTRR and MMADHC genes have not been ruled out. Homozygotes for this R369C are B6-responsive in a corrective dose of a daily multivitamins and presented with a mild phenotype or no symptoms. This may explain the high frequency of this variant in gnomAD database. The functional studies displayed discordant results when tested in the different expression systems. However, in all functional studies cells harboring the R369C showed moderately reduced activity and lower rate of a tetramer formation (active form) (Kim_1997, Janosick_2009, Kozich_2010, Mayfield_2012). The following publications have been ascertained in the context of this evaluation (PMID: 32245022, 30165906, 12124992, 22612060, 29205322, 18708589, 18950795, 29650765, 31301157, 9361025, 10364517, 20506325, 28152038, 22267502, 31664448, 25331909, 31139930, 19819175, 31211624, 36588553). ClinVar contains an entry for this variant (Variation ID: 212860). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.R369C variant (also known as c.1105C>T), located in coding exon 10 of the CBS gene, results from a C to T substitution at nucleotide position 1105. The arginine at codon 369 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in several individuals and cohorts with homocystinuria who were B6 responsive (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26). Newborn blood screening found this variant to be present at a frequency of approximately 0.8% and 0.5% in Norway and Czech, respectively (Refsum H et al. J. Pediatr., 2004 Jun;144:830-2; Janosík M et al. J. Pediatr., 2009 Mar;154:431-7). This variant was reported not to affect yeast growth (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21), but attenuated enzyme activity in E. coli and CHO-K1 cells to some extent (Janosík M et al. J. Pediatr., 2009 Mar;154:431-7). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 369 of the CBS protein (p.Arg369Cys). This variant is present in population databases (rs117687681, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pyridoxine-responsive homocystinuria (PMID: 9361025, 10364517, 12124992, 18950795). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212860). 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 expected to disrupt CBS protein function. Experimental studies have shown that this missense change affects CBS function (PMID: 10364517, 18708589, 18950795, 20506325). 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. -
Connective tissue disorder Uncertain:1
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CBS-related disorder Uncertain:1
The CBS c.1105C>T variant is predicted to result in the amino acid substitution p.Arg369Cys. This variant has been reported in the compound heterozygous state along with a second pathogenic variant in two individuals with CBS deficiency. Both of these patients were reported to be pyridoxine responsive with clinical presentations that ranged from asymptomatic to severe psychiatric disturbances (Kim et al. 1997. PubMed ID: 9361025; Gaustadnes et al. 2002. PubMed ID: 12124992). It has also been reported in the homozygous state in a patient with CBS deficiency, although that patient was also homozygous for a second missense variant in CBS (p.Arg491Cys; Kluijtmans et al. 1999. PubMed ID: 10364517). In addition, it was more recently reported with a second rare missense variant in CBS in a patient without clinical or biochemical features of homocystinuria. No additional segregation studies were performed for that patient (Kaadan et al. 2018. PubMed ID: 29650765). The c.1105C>T variant has been reported to be one of the most common CBS variants among Northern Europeans (Refsum et al. 2004. PubMed ID: 15192637; Janosík et al. 2009. PubMed ID: 18950795). Consistent with these reports, the c.1105C>T variant is listed in the gnomAD database at an allele frequency of ~0.5% in the European population, and 4 homozygotes are reported in this population group. In vitro functional studies have shown that the p.Arg369Cys change leads to a decrease in CBS activity relative to wild-type in E. coli and mammalian (CHO cells) expression systems, as well decreasing protein stability (Janosík et al. 2009. PubMed ID: 18950795; Kozich et al. 2010. PubMed ID: 20506325; Hnízda et al. 2012. PubMed ID: 22069143; Melenovská et al. 2015. PubMed ID: 25331909), although the p.Arg369Cys substitution seems to have no deleterious effect in a yeast expression system (Mayfield et al. 2012. PubMed ID: 22267502). Lastly, we have observed this variant internally in many individuals, some of whom had positive test results in other genes that explained their phenotype, and the majority of which had no second CBS variant identified. One patient was homozygous for the c.1105C>T variant and had some clinical features that could be consistent with CBS deficiency. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at